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Pancreatic Neoplasms: HELP
Articles by Erxi Wu
Based on 35 articles published since 2010
(Why 35 articles?)
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Between 2010 and 2020, E. Wu wrote the following 35 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Paracrine sonic hedgehog signaling derived from tumor epithelial cells: a key regulator in the pancreatic tumor microenvironment. 2012

Li, Xuqi / Ma, Qingyong / Duan, Wanxing / Liu, Han / Xu, Hongqin / Wu, Erxi. ·Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. ·Crit Rev Eukaryot Gene Expr · Pubmed #22856428.

ABSTRACT: Activation of the hedgehog (Hh) signaling pathway is involved in embryo development and tumorigenesis. While normal pancreatic tissue exhibits little Hh pathway activity, patients with pancreatic adenocarcinoma have high levels of Hh pathway signaling in both the tumor epithelia and the surrounding stromal tissue. Hh ligands expressed by pancreatic cancers promote tumor growth indirectly by activating Hh signaling in the surrounding stroma. This paracrine activation of Hh signaling in the tumor microenvironment provides a more favorable environment for tumor cellular proliferation, metastasis, and resistance to therapy. Taken together, these findings are of valuable implications for the use of Hh pathway inhibitors currently in development and inhibition of the Hh pathway paracrine loop in pancreatic cancer.

2 Review Advances in biomarker research for pancreatic cancer. 2012

Bhat, Kruttika / Wang, Fengfei / Ma, Qingyong / Li, Qinyu / Mallik, Sanku / Hsieh, Tze-Chen / Wu, Erxi. ·Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58108-6050, USA. ·Curr Pharm Des · Pubmed #22372502.

ABSTRACT: Pancreatic cancer (PC) is a leading cause of cancer related deaths in United States. The lack of early symptoms results in latestage detection and a high mortality rate. Currently, the only potentially curative approach for PC is surgical resection, which is often unsuccessful because the invasive and metastatic nature of the tumor masses makes their complete removal difficult. Consequently, patients suffer relapses from remaining cancer stem cells or drug resistance that eventually lead to death. To improve the survival rate, the early detection of PC is critical. Current biomarker research in PC indicates that a serum carbohydrate antigen, CA 19-9, is the only available biomarker with approximately 90% specificity to PC. However, the efficacy of CA 19-9 for assessing prognosis and monitoring patients with PC remains contentious. Thus, advances in technology and the detection of new biomarkers with high specificity to PC are needed to reduce the mortality rate of pancreatic cancer.

3 Review Targeting the cancer-stroma interaction: a potential approach for pancreatic cancer treatment. 2012

Li, Xuqi / Ma, Qingyong / Xu, Qinhong / Duan, Wanxing / Lei, Jianjun / Wu, Erxi. ·Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China. ·Curr Pharm Des · Pubmed #22372501.

ABSTRACT: Recent studies have demonstrated that the interaction between the cancer and the stroma, play a key role in the development of pancreatic cancer. The desmoplasia, which consists of fibroblasts, pancreatic stellate cells, lymphatic and vascular endothelial cells, immune cells, pathologic increased nerves, and the extracellular matrix (ECM), creates a complex tumor microenvironment that promotes pancreatic cancer development, invasion, metastasis, and resistance to chemotherapy. Thus, the potential approach for targeting the components of this desmoplastic reaction or the pancreatic tumor microenvironment might represent a novel therapeutic approach to advanced pancreatic carcinoma. Novel therapies that target on the pancreatic tumor microenvironment should become one of the more effective treatments for pancreatic cancer.

4 Review Therapeutic potential of perineural invasion, hypoxia and desmoplasia in pancreatic cancer. 2012

Liu, Han / Ma, Qingyong / Xu, Qinhong / Lei, Jianjun / Li, Xuqi / Wang, Zheng / Wu, Erxi. ·Department of Hepatobiliary Surgery, The First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China. ·Curr Pharm Des · Pubmed #22372500.

ABSTRACT: Pancreatic cancer is one of the most fatal human malignancies. Though a relatively rare malignancy, it remains one of the deadliest tumors, with an extremely high mortality rate. The prognosis of patients with pancreatic cancer remains poor; only patients with small tumors and complete resection have a chance of a complete cure. Pancreatic cancer responds poorly to conventional therapies, including chemotherapy and irradiation. Tumor-specific targeted therapy is a relatively recent addition to the arsenal of anti-cancer therapies. It is important to find novel targets to distinguish tumor cells from their normal counterparts in therapeutic approaches. In the past few decades, studies have revealed the molecular mechanisms of pancreatic tumorigenesis, growth, invasion and metastasis. The proteins that participate in the pathophysiological processes of pancreatic cancer might be potential targets for therapy. This review describes the main players in perineural invasion, hypoxia and desmoplasia and the molecular mechanisms of these pathophysiological processes.

5 Review Hyperglycemia as a mechanism of pancreatic cancer metastasis. 2012

Li, Wei / Ma, Qingyong / Liu, Jiangbo / Han, Liang / Ma, Guodong / Liu, Han / Shan, Tao / Xie, Keping / Wu, Erxi. ·Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, Shaanxi Province, China. ·Front Biosci (Landmark Ed) · Pubmed #22201834.

ABSTRACT: As a vital step in the progression of cancer, metastasis poses the largest problem in cancer treatment and is the main cause of death of cancer patients. In pancreatic cancer, almost 80% of patients have locally deteriorated or metastatic disease and thus are not appropriate for resection at the time of diagnosis. Due to the high rate of incidence and mortality, it is crucial to study the molecular mechanisms of metastasis to clarify therapeutic targets to hinder the spread of cancer. Diabetes mellitus has long been considered a potential risk factor for pancreatic cancer. In this review, we comprehensively describe the role of hyperglycemia in governing critical steps of the metastatic process. In particular, we focus on the hyperglycemia-dependent aspects of the Epithelial-Mesenchymal Transition (EMT) and vascular dysfunction. Furthermore, we discuss how hyperglycemia-related production of reactive oxygen species (ROS) may play an important role in these two processes. A deep understanding of metastasis mechanisms will identify novel targets for therapeutic intervention.

6 Article Sonic hedgehog signaling pathway promotes pancreatic cancer pain via nerve growth factor. 2020

Han, Liang / Jiang, Jie / Xue, Mengwen / Qin, Tao / Xiao, Ying / Wu, Erxi / Shen, Xin / Ma, Qingyong / Ma, Jiguang. ·Department of Hepatobiliary Surgery, Xi'an Jiaotong University Medical College First Affiliated Hospital, Xi'an, Shaanxi, China. · Department of Medical Oncology, Shaanxi Provincial People's Hospital, Xi'an, China. · Department of Anesthesiology, Xi'an Jiaotong University Medical College First Affiliated Hospital, Xi'an, China. · Department of Surgery, Baylor Scott and White Health, Dallas, Texas, USA. · Department of Neurosurgery, Baylor Scott and White Health, Dallas, Texas, USA. · Department of Hepatobiliary Surgery, Xi'an Jiaotong University Medical College First Affiliated Hospital, Xi'an, Shaanxi, China qyma56@xjtu.edu.cn. ·Reg Anesth Pain Med · Pubmed #31792027.

ABSTRACT: BACKGROUND: Many patients with pancreatic cancer (PC) suffer from abdominal pain and back pain. However, the cause of pain associated with PC is largely unclear. In this study, we tested the potential influence of the sonic hedgehog (sHH) signaling pathway on PC pain. METHODS: Substance P (SP) and calcitonin gene-related peptide (CGRP) expression was measured in cultured PC cells and dorsal root ganglions (DRG) by real-time PCR, western blotting analysis and ELISA. Small interfering RNA transfection and plasmid constructs were used to regulate the expression of sHH in the AsPc-1 and Panc-1 cell lines. Pain-related behavior was observed in an orthotopic tumor model in nude mice. RESULTS: In this study, the results show that sHH increased the expression of SP and CGRP in DRGs in a concentration and time-dependent manner. Additionally, sHH secretion from PC cells could activate the sHH signaling pathway and, in turn, increase the expression of nerve growth factor (NGF), P75, and TrkA in DRGs. Furthermore, the sHH signaling pathway and NGF/NGF receptor contributed to pain sensitivity in a nude mouse model. CONCLUSION: Our results demonstrate that PC pain originates from the sHH signaling pathway, and NGF mediates the pain mechanism via regulating SP and CGRP.

7 Article Betulinic acid inhibits stemness and EMT of pancreatic cancer cells via activation of AMPK signaling. 2019

Sun, Liankang / Cao, Junyu / Chen, Ke / Cheng, Liang / Zhou, Cancan / Yan, Bin / Qian, Weikun / Li, Jie / Duan, Wanxing / Ma, Jiguang / Qi, Dan / Wu, Erxi / Wang, Zheng / Liu, Qingguang / Ma, Qingyong / Xu, Qinhong. ·Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China. · Department of Anesthesiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China. · 3Department of Neurosurgery, Baylor Scott & White Health, Temple, TX 78508, USA. · Department of Geriatric Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China. ·Int J Oncol · Pubmed #30365057.

ABSTRACT: Cancer stem cells (CSCs), which are found in various types of human cancer, including pancreatic cancer, possess elevated metastatic potential, lead to tumor recurrence and cause chemoradiotherapy resistance. Alterations in cellular bioenergetics through the regulation of 5' adenosine monophosphate‑activated protein kinase (AMPK) signaling may be a prerequisite to stemness. Betulinic acid (BA) is a well‑known bioactive compound with antiretroviral and anti‑inflammatory potential, which has been reported to exert anticancer effects on various types of cancer, including pancreatic cancer. The present study aimed to investigate whether BA could inhibit pancreatic CSCs via regulation of AMPK signaling. The proliferation of pancreatic cancer cells was examined by MTT and colony formation assays. The migratory and invasive abilities of pancreatic cancer cells were assessed using wound‑scratch and Transwell invasion assays. In addition, the expression levels of candidate genes were measured by reverse transcription‑quantitative polymerase chain reaction and western blotting. The results revealed that BA inhibited the proliferation and tumorsphere formation of pancreatic cancer cells, suppressed epithelial‑mesenchymal transition (EMT), migration and invasion, and reduced the expression of three pluripotency factors [SRY‑box 2 (Sox2), octamer‑binding protein 4 (Oct4) and Nanog]. Furthermore, immunohistochemical analysis confirmed that there was a significant inverse association between the expression levels of phosphorylated (P)‑AMPK and Sox2 in pancreatic cancer, and it was revealed that BA may activate AMPK signaling. Notably, knockdown of AMPK reversed the suppressive effects of BA on EMT and stemness of pancreatic cancer cells. In addition, BA reversed the effects of gemcitabine on stemness and enhanced the sensitivity of pancreatic cancer cells to gemcitabine. Collectively, these results indicated that BA may effectively inhibit pluripotency factor expression (Sox2, Oct4 and Nanog), EMT and the stem‑like phenotype of pancreatic cancer cells via activating AMPK signaling. Therefore, BA may be considered an attractive therapeutic candidate and an effective inhibitor of the stem‑like phenotype in pancreatic cancer cells. Further investigation into the development of BA as an anticancer drug is warranted.

8 Article Resveratrol enhances the chemotherapeutic response and reverses the stemness induced by gemcitabine in pancreatic cancer cells via targeting SREBP1. 2019

Zhou, Cancan / Qian, Weikun / Ma, Jiguang / Cheng, Liang / Jiang, Zhengdong / Yan, Bin / Li, Jie / Duan, Wanxing / Sun, Liankang / Cao, Junyu / Wang, Fengfei / Wu, Erxi / Wu, Zheng / Ma, Qingyong / Li, Xuqi. ·Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China. · Department of Anesthesiology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China. · Department of Neurosurgery, Neuroscience Institute, Baylor Scott and White Health, Temple, Texas. · Neuroscience Institute, Baylor Scott & White Health, Temple, Texas. · Department of Surgery, Texas A & M University Health Science Center, College of Medicine, Temple, Texas. · Department of Neurology, Baylor Scott & White Health, Temple, Texas. · Department of Pharmaceutical Sciences, Texas A & M University College of Pharmacy, College Station, Texas. · Department of General Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China. ·Cell Prolif · Pubmed #30341797.

ABSTRACT: OBJECTIVES: Gemcitabine is a standard treatment for advanced pancreatic cancer patients but can cause chemoresistance during treatment. The chemoresistant cells have features of cancer stem cells (CSCs). Resveratrol has been reported to overcome the resistance induced by gemcitabine. However, the mechanism by which resveratrol enhances chemosensitivity remains elusive. Here, we explored the mechanism by which resveratrol enhanced chemosensitivity and the role of sterol regulatory element binding protein 1 (SREBP1) in gemcitabine-induced stemness. MATERIALS AND METHODS: The pancreatic cancer cell lines MiaPaCa-2 and Panc-1 were treated under different conditions. Methyl thiazolyl tetrazolium and colony formation assays were performed to evaluate effects on proliferation. Flow cytometry was conducted to detect apoptosis. Oil red O staining was performed to examine lipid synthesis. The sphere formation assay was applied to investigate the stemness of cancer cells. Immunohistochemistry was performed on tumour tissue obtained from treated KPC mice. RESULTS: Resveratrol enhanced the sensitivity of gemcitabine and inhibited lipid synthesis via SREBP1. Knockdown of SREBP1 limited the sphere formation ability and suppressed the expression of CSC markers. Furthermore, suppression of SREBP1 induced by resveratrol reversed the gemcitabine-induced stemness. These results were validated in a KPC mouse model. CONCLUSIONS: Our data provide evidence that resveratrol reverses the stemness induced by gemcitabine by targeting SREBP1 both in vitro and in vivo. Thus, resveratrol can be an effective chemotherapy sensitizer, and SREBP1 may be a rational therapeutic target.

9 Article Targeting glypican-4 overcomes 5-FU resistance and attenuates stem cell-like properties via suppression of Wnt/β-catenin pathway in pancreatic cancer cells. 2018

Cao, Junyu / Ma, Jiguang / Sun, Liankang / Li, Jie / Qin, Tao / Zhou, Cancan / Cheng, Liang / Chen, Ke / Qian, Weikun / Duan, Wanxing / Wang, Fengfei / Wu, Erxi / Wang, Zheng / Ma, Qingyong / Han, Liang. ·Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China. · Department of Anesthesiology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China. · Department of Neurosurgery, Baylor Scott & White Health, Temple, Texas. · Neuroscience Institute, Baylor Scott & White Health, Temple, Texas. · Department of Surgery, Texas A & M University College of Medicine, College Station, Texas. · Department of Neurology, Baylor Scott & White Health, Temple, Texas. · Department of Pharmaceutical Sciences, Texas A & M University College of Pharmacy, College Station, Texas. ·J Cell Biochem · Pubmed #30010221.

ABSTRACT: The existences of cancer stem cells in patients with pancreatic cancer are considered as pivotal factors contributing to chemoresistance and disease relapse. Glypican-4 (GPC4) is one of the members of the glypicans family, which underlies human congenital malformations and multiple diseases. However, its potential biological function in pancreatic cancer still remains elusive. In this study, we are the first to demonstrate that GPC4 was involved in 5-fluorouracil (5-FU) resistance and pancreatic cancer stemness through comprehensive bioinformatical analysis. Functional experiments showed that knockdown of GPC4 sensitized pancreatic cancer cells to 5-FU and attenuated stem cell-like properties. In terms of mechanism research, knockdown of GPC4 suppressed the activation of Wnt/β-catenin pathway and its downstream targets. Furthermore, the expression of GPC4 was significantly upregulated in pancreatic cancer tissues compared with normal tissues and remarkably correlated with patients' overall survival according to the data derived from the Cancer Genome Atlas database. Taken together, our results suggest that GPC4 is a key regulator in chemoresistance and pancreatic cancer stemness. Thus, targeting GPC4 may serve as a promising strategy for pancreatic cancer therapy.

10 Article Desmoplasia suppression by metformin-mediated AMPK activation inhibits pancreatic cancer progression. 2017

Duan, Wanxing / Chen, Ke / Jiang, Zhengdong / Chen, Xin / Sun, Liankang / Li, Jiahui / Lei, Jianjun / Xu, Qinhong / Ma, Jiguang / Li, Xuqi / Han, Liang / Wang, Zheng / Wu, Zheng / Wang, Fengfei / Wu, Erxi / Ma, Qingyong / Ma, Zhenhua. ·Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China. · Department of Anesthesiology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China. · Department of General Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China. · Department of Neurosurgery, Baylor Scott & White Health, Temple 76508, TX, USA. · Department of Neurosurgery, Baylor Scott & White Health, Temple 76508, TX, USA; Department of Surgery, Texas A & M Health Science Center College of Medicine, Temple 76504, TX, USA; Department of Pharmaceutic Sciences, Texas A & M Health Science Center College of Pharmacy, College Station 77843, TX, USA. · Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: qyma56@mail.xjtu.edu.cn. ·Cancer Lett · Pubmed #27773749.

ABSTRACT: Emerging evidence suggests that metformin, an activator of AMP-activated protein kinase (AMPK), may be useful in preventing and treating pancreatic ductal adenocarcinoma (PDAC). However, whether metformin has an effect on the stromal reaction of PDAC remains unknown. In this study, we first evaluated the expression of AMPK and phosphorylated-AMPK (P-AMPK) in normal and PDAC tissues, our data indicate that reduced P-AMPK expression is a frequent event in PDAC and correlated with poor prognosis and the dense stromal reaction. We then determined the efficacy of metformin on PDAC growth in vitro and in vivo. We reveal that metformin reduces the production of fibrogenic cytokines from pancreatic cancer cells (PCs) and inhibits paracrine-mediated pancreatic stellate cells (PSCs) activation under PCsPSCs co-culture conditions. By using a xenograft PDAC mouse model, we show that metformin intervention prevents tumor growth and enhances the antitumor effect of gemcitabine via suppression of desmoplastic reaction. Taken together, these results suggest that induction of AMPK activation by metformin represents a novel therapeutic approach for treating advanced PDAC through reducing the desmoplastic reaction in PDAC.

11 Article Pancreatic stellate cells contribute pancreatic cancer pain via activation of sHH signaling pathway. 2016

Han, Liang / Ma, Jiguang / Duan, Wanxing / Zhang, Lun / Yu, Shuo / Xu, Qinhong / Lei, Jianjun / Li, Xuqi / Wang, Zheng / Wu, Zheng / Huang, Jason H / Wu, Erxi / Ma, Qingyong / Ma, Zhenhua. ·Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. · Department of Anesthesiology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. · Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. · Department of Neurosurgery, Baylor Scott and White Health Care, Temple, TX, 76508, USA. · Department of Surgery, Texas A & M College of Medicine, Temple, TX, 76504, USA. · Department of Pharmaceutical Sciences, Texas A & M Health Science Center, College Station, TX, 77843, USA. ·Oncotarget · Pubmed #26934446.

ABSTRACT: Abdominal pain is a critical clinical symptom in pancreatic cancer (PC) that affects the quality of life for PC patients. However, the pathogenesis of PC pain is largely unknown. In this study, we show that PC pain is initiated by the sonic hedgehog (sHH) signaling pathway in pancreatic stellate cells (PSCs), which is activated by sHH secreted from PC cells, and then, neurotrophic factors derived from PSCs mediate the pain. The different culture systems were established in vitro, and the expression of sHH pathway molecules, neurotrophic factors, TRPV1, and pain factors were examined. Capsaicin-evoked TRPV1 currents in dorsal root ganglion (DRG) neurons were examined by the patch-clamp technique. Pain-related behavior was observed in an orthotopic tumor model. sHH and PSCs increased the expression and secretion of TRPV1, SP, and CGRP by inducing NGF and BDNF in a co-culture system, also increasing TRPV1 current. But, suppressing sHH pathway or NGF reduced the expression of TRPV1, SP, and CGRP. In vivo, PSCs and PC cells that expressed high levels of sHH could enhance pain behavior. Furthermore, the blockade of NGF or TRPV1 significantly attenuated the pain response to mechanical stimulation compared with the control. Our results demonstrate that sHH signaling pathway is involved in PC pain, and PSCs play an essential role in the process greatly by inducing NGF.

12 Article β2-adrenogenic signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α. 2016

Zhang, Dong / Lei, Jianjun / Ma, Jiguang / Chen, Xin / Sheng, Liang / Jiang, Zhengdong / Nan, Ligang / Xu, Qinhong / Duan, Wanxing / Wang, Zheng / Li, Xuqi / Wu, Zheng / Wu, Erxi / Ma, Qingyong / Huo, Xiongwei. ·Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. · Department of Oncology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. · Department of General Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, China. · Department of Neurosurgery, Baylor Scott and White Health, Temple, TX, 76508, USA. ·Oncotarget · Pubmed #26497365.

ABSTRACT: Cigarette smoking is a risk factor for pancreatic cancer. It is suggested that 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), a tobacco-specific nitrosamine, mediates the carcinogenic action of cigarette smoking by promoting cancer growth. In the present study, we show that smoking, HIF-1α expression and β2-adrenogenic receptor (β2-AR) expression are negatively correlated with the overall survival of pancreatic cancer patients. Moreover, HIF-1α expression and β2-AR expression are positively correlated with smoking status, different histological differentiation and among the tumor node metastasis (TNM) stages in pancreatic cancer patients. NNK increases HIF-1α expression in pancreatic cancer in vitro and in vivo. Furthermore, knockdown of HIF-1α and ICI118, 551 (a β2-AR selective antagonist) abrogates NNK-induced pancreatic cancer proliferation and invasion in vitro and inhibits NNK-induced pancreatic cancer growth in vivo. However, using CoCl2 (a HIF-1α stabilizing agent which decreases HIF-1α degradation under normoxia conditions) reverses ICI118, 551 induced effects under NNK exposure. Thus, our data indicate that β2-AR signaling regulates NNK-induced pancreatic cancer progression via upregulation of HIF-1α. Taken together, β2-AR signaling and HIF-1α may represent promising therapeutic targets for preventing smoking induced pancreatic cancer progression.

13 Article Hydrogen peroxide mediates hyperglycemia-induced invasive activity via ERK and p38 MAPK in human pancreatic cancer. 2015

Li, Wei / Ma, Zhenhua / Ma, Jiguang / Li, Xuqi / Xu, Qinhong / Duan, Wanxing / Chen, Xin / Lv, Yunfu / Zhou, Shuang / Wu, Erxi / Ma, Qingyong / Huo, Xiongwei. ·Department of Hepatobiliary Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. · Department of Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. · Department of General Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. · Department of General Surgery, People's Hospital of Hainan Province, Haikou, 570311, China. · Department of Pharmaceutical Sciences, North Dakota State University, Fargo, 58108, ND, USA. ·Oncotarget · Pubmed #26439801.

ABSTRACT: Diabetes mellitus and pancreatic cancer are intimately related, as approximately 85% of pancreatic cancer patients suffer from glucose intolerance or even diabetes. In this study, we evaluate the underlying mechanism by which hyperglycemia modulates the invasive potential of cancer cells and contributes to their enhanced metastatic behavior. Here we show that hyperglycemia increases the hydrogen peroxide (H2O2) concentration through up-regulation of manganese superoxide dismutase (SOD2) expression, which further activates the ERK and p38 MAPK pathways, as well as the transcription factors NF-κB and AP-1, in a time-dependent manner. The invasion of pancreatic cancer cells resulting from the activation of the H2O2/MAPK axis under high glucose conditions is effectively inhibited by PD 98059 (ERK inhibitor), SB 203580 (p38 MAPK inhibitor), polyethylene glycol-conjugated catalase (PEG-CAT), or the siRNA specific to SOD2. In addition, streptozotocin-treated diabetic nude mice exhibit a stronger tumor invasive ability in renal capsule xenografts which could be suppressed by PEG-CAT treatment. Furthermore, the integrated optical density (IOD) of SOD2 and uPA stainings is higher in the tumor tissues of pancreatic cancer patients with diabetes compared with pancreatic cancer patients with euglycemia. Taken together, our results demonstrate that hyperglycemia enhances cell invasive ability through the SOD2/H2O2/MAPK axis in human pancreatic cancer. Thus, SOD2/H2O2/MAPK axis may represent a promising therapeutic target for pancreatic cancer patients combined with diabetes mellitus.

14 Article Hyperglycemic tumor microenvironment induces perineural invasion in pancreatic cancer. 2015

Li, Junhui / Ma, Jiguang / Han, Liang / Xu, Qinhong / Lei, Jianjun / Duan, Wanxing / Li, Wei / Wang, Fengfei / Wu, Erxi / Ma, Qingyong / Huo, Xiongwei. ·a Department of Hepatobiliary Surgery ; First Affiliated Hospital of Medical College; Xi'an Jiaotong University ; Xi'an , China. ·Cancer Biol Ther · Pubmed #25946624.

ABSTRACT: Glucose intolerance and frank diabetes mellitus (DM) can increase the risk of cancer death for pancreatic cancer (PanCa). However, the mechanism by which these factors influence cancer deaths is not clear. In this study, we established a model system to mimic the pancreatic tumor microenvironment in patients with DM to examine the biological behavior of PanCa cells and nerves in cell culture and in animals. Our in vitro studies demonstrated that hyperglycemia promoted the proliferation and invasion of PanCa cell lines and upregulated the expression of nerve growth factor in these cells. Also, the migration of Schwann cells (SCs) was inhibited by hyperglycemia and neurites exerted pathological regeneration. Furthermore, the interaction between the PanCa cells and nerves was enhanced in the tumor microenvironment. We further showed that hyperglycemia promoted the perineural invasion (PNI) of PanCa in vivo. These data suggest that DM worsens the prognosis of PanCa because of aggravated PNI. Thus, our study illustrates a novel mechanism by which hyperglycemia decreases survival in patients with PanCa.

15 Article Ginkgolic acid suppresses the development of pancreatic cancer by inhibiting pathways driving lipogenesis. 2015

Ma, Jiguang / Duan, Wanxing / Han, Suxia / Lei, Jianjun / Xu, Qinhong / Chen, Xin / Jiang, Zhengdong / Nan, Ligang / Li, Jiahui / Chen, Ke / Han, Liang / Wang, Zheng / Li, Xuqi / Wu, Erxi / Huo, Xiongwei. ·Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China. · Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China. · Department of General Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China. · Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA. ·Oncotarget · Pubmed #25895130.

ABSTRACT: Ginkgolic acid (GA) is a botanical drug extracted from the seed coat of Ginkgo biloba L. with a wide range of bioactive properties, including anti-tumor effect. However, whether GA has antitumor effect on pancreatic cancer cells and the underlying mechanisms have yet to be investigated. In this study, we show that GA suppressed the viability of cancer cells but has little toxicity on normal cells, e.g, HUVEC cells. Furthermore, treatment of GA resulted in impaired colony formation, migration, and invasion ability and increased apoptosis of cancer cells. In addition, GA inhibited the de novo lipogenesis of cancer cells through inducing activation of AMP-activated protein kinase (AMPK) signaling and downregulated the expression of key enzymes (e.g. acetyl-CoA carboxylase [ACC], fatty acid synthase [FASN]) involved in lipogenesis. Moreover, the in vivo experiment showed that GA reduced the expression of the key enzymes involved in lipogenesis and restrained the tumor growth. Taken together, our results suggest that GA may serve as a new candidate against tumor growth of pancreatic cancer partially through targeting pathway driving lipogenesis.

16 Article Stromal-derived factor-1α/CXCL12-CXCR4 chemotactic pathway promotes perineural invasion in pancreatic cancer. 2015

Xu, Qinhong / Wang, Zheng / Chen, Xin / Duan, Wanxing / Lei, Jianjun / Zong, Liang / Li, Xuqi / Sheng, Liang / Ma, Jiguang / Han, Liang / Li, Wei / Zhang, Lun / Guo, Kun / Ma, Zhenhua / Wu, Zheng / Wu, Erxi / Ma, Qingyong. ·Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. · Department of General Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. · Department of Oncology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. · Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA. ·Oncotarget · Pubmed #25605248.

ABSTRACT: Perineural invasion (PNI) is considered as an alternative route for the metastatic spread of pancreatic cancer cells; however, the molecular changes leading to PNI are still poorly understood. In this study, we show that the CXCL12/CXCR4 axis plays a pivotal role in the neurotropism of pancreatic cancer cells to local peripheral nerves. Immunohistochemical staining results revealed that CXCR4 elevation correlated with PNI in 78 pancreatic cancer samples. Both in vitro and in vivo PNI models were applied to investigate the function of the CXCL12/CXCR4 signaling in PNI progression and pathogenesis. The results showed that the activation of the CXCL12/CXCR4 axis significantly increased pancreatic cancer cells invasion and promoted the outgrowth of the dorsal root ganglia. CXCL12 derived from the peripheral nerves stimulated the invasion and chemotactic migration of CXCR4-positive cancer cells in a paracrine manner, eventually leading to PNI. In vivo analyses revealed that the abrogation of the activated signaling inhibited tumor growth and invasion of the sciatic nerve toward the spinal cord. These data indicate that the CXCL12/CXCR4 axis may be a novel therapeutic target to prevent the perineural dissemination of pancreatic cancer.

17 Article Overexpression of Nodal induces a metastatic phenotype in pancreatic cancer cells via the Smad2/3 pathway. 2015

Duan, Wanxing / Li, Rong / Ma, Jiguang / Lei, Jianjun / Xu, Qinhong / Jiang, Zhengdong / Nan, Ligang / Li, Xuqi / Wang, Zheng / Huo, Xiongwei / Han, Liang / Wu, Zheng / Wu, Erxi / Ma, Qingyong. ·Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China. · Department of Pediatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. · Department of Oncology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China. · Department of General Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China. · Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota 58105, USA. ·Oncotarget · Pubmed #25557170.

ABSTRACT: Metastasis is the major cause for the high mortality rate of pancreatic cancer. Human embryonic stem cell (hESC) associated genes frequently correlate with malignant disease progression. Recent studies have demonstrated that the embryonic protein Nodal, which plays a critical role during embryonic development, is re-expressed in several types of tumors and promotes cancers progression. However, little is known about the role of Nodal in pancreatic cancer. Here, we show that Nodal expression is upregulated in human pancreatic cancer tissues. Moreover, Nodal expression levels correlate well with the grade of pancreatic cancer differentiation. In addition, we present clear evidence that Nodal induces signal transduction through the Smad2/3-dependent pathway in vitro. Furthermore, we show that Nodal promotes pancreatic cancer cell migration and invasion, induces epithelial-mesenchymal transition (EMT) and enhances the expression of matrix metalloproteinase-2 (MMP2) and CXC chemokine receptor 4 (CXCR4). Using an in vivo liver metastasis model of pancreatic cancer, we observed that blocking Nodal signaling activity with the small-molecule inhibitor SB431542 decreases the number and size of liver metastases. Taken together, our results suggest that Nodal overexpression induces a metastatic phenotype in pancreatic cancer cells, and that targeting Nodal signaling may be a promising therapeutic strategy for pancreatic cancer.

18 Article Arginine deiminase augments the chemosensitivity of argininosuccinate synthetase-deficient pancreatic cancer cells to gemcitabine via inhibition of NF-κB signaling. 2014

Liu, Jiangbo / Ma, Jiguang / Wu, Zheng / Li, Wei / Zhang, Dong / Han, Liang / Wang, Fengfei / Reindl, Katie M / Wu, Erxi / Ma, Qingyong. ·Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical college of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an, Shaanxi 710061, China. qyma56@mail.xjtu.edu.cn. ·BMC Cancer · Pubmed #25240403.

ABSTRACT: BACKGROUND: Pancreatic cancer is a leading cause of cancer-related deaths in the world with a 5-year survival rate of less than 6%. Currently, there is no successful therapeutic strategy for advanced pancreatic cancer, and new effective strategies are urgently needed. Recently, an arginine deprivation agent, arginine deiminase, was found to inhibit the growth of some tumor cells (i.e., hepatocellular carcinoma, melanoma, and lung cancer) deficient in argininosuccinate synthetase (ASS), an enzyme used to synthesize arginine. The purpose of this study was to evaluate the therapeutic efficacy of arginine deiminase in combination with gemcitabine, the first line chemotherapeutic drug for patients with pancreatic cancer, and to identify the mechanisms associated with its anticancer effects. METHODS: In this study, we first analyzed the expression levels of ASS in pancreatic cancer cell lines and tumor tissues using immunohistochemistry and RT-PCR. We further tested the effects of the combination regimen of arginine deiminase with gemcitabine on pancreatic cancer cell lines in vitro and in vivo. RESULTS: Clinical investigation showed that pancreatic cancers with reduced ASS expression were associated with higher survivin expression and more lymph node metastasis and local invasion. Treatment of ASS-deficient PANC-1 cells with arginine deiminase decreased their proliferation in a dose- and time-dependent manner. Furthermore, arginine deiminase potentiated the antitumor effects of gemcitabine on PANC-1 cells via multiple mechanisms including induction of cell cycle arrest in the S phase, upregulation of the expression of caspase-3 and 9, and inhibition of activation of the NF-κB survival pathway by blocking NF-κB p65 signaling via suppressing the nuclear translocation and phosphorylation (serine 536) of NF-κB p65 in vitro. Moreover, arginine deiminase can enhance antitumor activity of gemcitabine-based chemotherapy in the mouse xenograft model. CONCLUSIONS: Our results suggest that arginine deprivation by arginine deiminase, in combination with gemcitabine, may offer a novel effective treatment strategy for patients with pancreatic cancer and potentially improve the outcome of patients with pancreatic cancer.

19 Article Sonic hedgehog paracrine signaling activates stromal cells to promote perineural invasion in pancreatic cancer. 2014

Li, Xuqi / Wang, Zheng / Ma, Qingyong / Xu, Qinhong / Liu, Han / Duan, Wanxing / Lei, Jianjun / Ma, Jiguang / Wang, Xiu / Lv, Shifang / Han, Liang / Li, Wei / Guo, Jian / Guo, Kun / Zhang, Dong / Wu, Erxi / Xie, Keping. ·Departments of Hepatobiliary Surgery, General Surgery, and. · Departments of Hepatobiliary Surgery. · Departments of Hepatobiliary Surgery, qyma56@mail.xjtu.edu.cn kepxie@mdanderson.org. · Oncology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi, China; · Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota; and. · Department of Gastroenterology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas qyma56@mail.xjtu.edu.cn kepxie@mdanderson.org. ·Clin Cancer Res · Pubmed #24947933.

ABSTRACT: PURPOSE: Pancreatic cancer is characterized by stromal desmoplasia and perineural invasion (PNI). We sought to explore the contribution of pancreatic stellate cells (PSC) activated by paracrine Sonic Hedgehog (SHH) in pancreatic cancer PNI and progression. EXPERIMENTAL DESIGN: In this study, the expression dynamics of SHH were examined via immunohistochemistry, real-time PCR, and Western blot analysis in a cohort of carcinomatous and nonneoplastic pancreatic tissues and cells. A series of in vivo and in vitro assays was performed to elucidate the contribution of PSCs activated by paracrine SHH signaling in pancreatic cancer PNI and progression. RESULTS: We show that SHH overexpression in tumor cells is involved in PNI in pancreatic cancer and is an important marker of biologic activity of pancreatic cancer. Moreover, the overexpression of SHH in tumor cells activates the hedgehog pathway in PSCs in the stroma instead of activating tumor cells. These activated PSCs are essential for the promotion of pancreatic cancer cell migration along nerve axons and nerve outgrowth to pancreatic cancer cell colonies in an in vitro three-dimensional model of nerve invasion in cancer. Furthermore, the coimplantation of PSCs activated by paracrine SHH induced tumor cell invasion of the trunk and nerve dysfunction along sciatic nerves and also promoted orthotropic xenograft tumor growth, metastasis, and PNI in in vivo models. CONCLUSIONS: These results establish that stromal PSCs activated by SHH paracrine signaling in pancreatic cancer cells secrete high levels of PNI-associated molecules to promote PNI in pancreatic cancer.

20 Article α-Mangostin suppresses the viability and epithelial-mesenchymal transition of pancreatic cancer cells by downregulating the PI3K/Akt pathway. 2014

Xu, Qinhong / Ma, Jiguang / Lei, Jianjun / Duan, Wanxing / Sheng, Liang / Chen, Xin / Hu, Ang / Wang, Zheng / Wu, Zheng / Wu, Erxi / Ma, Qingyong / Li, Xuqi. ·Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. · Department of Oncology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. · Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA. · Department of General Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China. ·Biomed Res Int · Pubmed #24812621.

ABSTRACT: α -Mangostin, a natural product isolated from the pericarp of the mangosteen fruit, has been shown to inhibit the growth of tumor cells in various types of cancers. However, the underlying molecular mechanisms are largely unclear. Here, we report that α -mangostin suppressed the viability and epithelial-mesenchymal transition (EMT) of pancreatic cancer cells through inhibition of the PI3K/Akt pathway. Treatment of pancreatic cancer BxPc-3 and Panc-1 cells with α -mangostin resulted in loss of cell viability, accompanied by enhanced cell apoptosis, cell cycle arrest at G1 phase, and decrease of cyclin-D1. Moreover, Transwell and Matrigel invasion assays showed that α -mangostin significantly reduced the migration and invasion of pancreatic cancer cells. Consistent with these results, α -mangostin decreased the expression of MMP-2, MMP-9, N-cadherin, and vimentin and increased the expression of E-cadherin. Furthermore, we found that α -mangostin suppressed the activity of the PI3K/Akt pathway in pancreatic cancer cells as demonstrated by the reduction of the Akt phosphorylation by α -mangostin. Finally, α -mangostin significantly inhibited the growth of BxPc-3 tumor mouse xenografts. Our results suggest that α -mangostin may be potentially used as a novel adjuvant therapy or complementary alternative medicine for the management of pancreatic cancers.

21 Article The Activation of β1-integrin by Type I Collagen Coupling with the Hedgehog Pathway Promotes the Epithelial-Mesenchymal Transition in Pancreatic Cancer. 2014

Duan, Wanxing / Ma, Jiguang / Ma, Qingyong / Xu, Qinhong / Lei, Jianjun / Han, Liang / Li, Xuqi / Wang, Zheng / Wu, Zheng / Lv, Shifang / Ma, Zhenhua / Liu, Mouzhu / Wang, Fengfei / Wu, Erxi. ·Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College, Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, China. qyma56@mail.xjtu.edu.cn. ·Curr Cancer Drug Targets · Pubmed #24720337.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by the excessive deposition of extracellular matrix (ECM), which is thought to contribute to this tumor's malignant behavior. However, the detailed mechanism and the contribution of excessive deposition of ECM in PDAC progression remain unclear. A better understanding of the mechanism involved in this process is essential for the design of new effective therapies. In this study, we demonstrated that pancreatic cancer cells exhibited increased proliferation and decreased apoptosis in response to type I collagen. In addition, PDAC cells exposed to type I collagen lost the expression of E-cadherin and increased expression of mesenchymal markers, including N-cadherin and vimentin. This epithelial- mesenchymal transition (EMT) was correlated with enhanced cell migration and invasiveness. Knockdown of β1-integrin abolished the effects induced by type I collagen, and further investigation revealed that type I collagen activates β1-integrin (marked by phosphorylation of β1 integrin downstream effectors, focal adhesion kinase [FAK], AKT, and ERK) accompanied by markedly up-regulation of Gli-1, a component of the Hedgehog (HH) pathway. Knockdown of Gli-1 reversed the effects of type I collagen on PDAC invasion and EMT. These results suggest that there is cross-talk between the β1-integrin signaling pathway and the HH pathway in pancreatic cancer and that activation of the HH pathway plays a key role in the type I collagen-induced effects on pancreatic cancer.

22 Article Hyperglycemia regulates TXNIP/TRX/ROS axis via p38 MAPK and ERK pathways in pancreatic cancer. 2014

Li, Wei / Wu, Zheng / Ma, Qingyong / Liu, Jiangbo / Xu, Qinhong / Han, Liang / Duan, Wanxing / Lv, Yunfu / Wang, Fengfei / Reindl, Katie M / Wu, Erxi. ·Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, China. qyma56@mail.xjtu.edu.cn. ·Curr Cancer Drug Targets · Pubmed #24720336.

ABSTRACT: Approximately 85% of pancreatic cancer patients suffer from glucose intolerance or even diabetes because high glucose levels can contribute to oxidative stress which promotes tumor development. As one of the reactive oxygen species (ROS)-regulating factors, thioredoxin-interacting protein (TXNIP), is involved in the maintenance of thioredoxin (TRX)-mediated redox regulation. In this study, we demonstrated that high glucose levels increased the expression of TXNIP in time- and concentration-dependent manners and modulated the activity of TRX and ROS production in pancreatic cancer cells, BxPC-3 and Panc-1. We also found that glucose activated both p38 MAPK and ERK pathways and inhibitors of these pathways impaired the TXNIP/TRX/ROS axis. Knockdown of TXNIP restored TRX activity and decreased ROS production under high glucose conditions. Moreover, we observed that the integrated optical density (IOD) of TXNIP staining as well as the protein and mRNA expression levels of TXNIP were higher in the tumor tissues of pancreatic cancer patients with diabetes. Taken together, these results indicate that hyperglycemia-induced TXNIP expression is involved in diabetes-mediated oxidative stress in pancreatic cancer via p38 MAPK and ERK pathways.

23 Article α-Mangostin inhibits hypoxia-driven ROS-induced PSC activation and pancreatic cancer cell invasion. 2014

Lei, Jianjun / Huo, Xiongwei / Duan, Wanxing / Xu, Qinhong / Li, Rong / Ma, Jiguang / Li, Xuqi / Han, Liang / Li, Wei / Sun, Hao / Wu, Erxi / Ma, Qingyong. ·Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, Shaanxi Province, China. · Department of General Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, Shaanxi Province, China. · Department of Oncology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, Shaanxi Province, China. · Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, Shaanxi Province, China. Electronic address: sunhaoxjyf@126.com. · Department of Pharmaceutical Sciences, North Dakota State University, Fargo, USA. · Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, 277 West Yanta Road, Xi'an 710061, Shaanxi Province, China. Electronic address: qyma56@mail.xjtu.edu.cn. ·Cancer Lett · Pubmed #24513179.

ABSTRACT: Recent advances indicating a key role of microenvironment for tumor progression, we investigated the role of PSCs and hypoxia in pancreatic cancer aggressiveness, and examined the potential protective effect of α-mangostin on hypoxia-driven pancreatic cancer progression. Our data indicate that hypoxic PSCs exploit their oxidative stress due to hypoxia to secrete soluble factors favouring pancreatic cancer invasion. α-Mangostin suppresses hypoxia-induced PSC activation and pancreatic cancer cell invasion through the inhibition of HIF-1α stabilization and GLI1 expression. Increased generation of hypoxic ROS is responsible for HIF-1α stabilization and GLI1 upregulation. Therefore, α-mangostin may be beneficial in preventing hypoxia-induced pancreatic cancer progression.

24 Article Indometacin ameliorates high glucose-induced proliferation and invasion via modulation of e-cadherin in pancreatic cancer cells. 2013

Han, Liang / Peng, Bo / Ma, Qingyong / Ma, Jiguang / Li, Juntao / Li, Wei / Duan, Wanxing / Chen, Chao / Liu, Jiangbo / Xu, Qinhong / Laporte, Kyle / Li, Zehui / Wu, Erxi. ·Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. · Emergency Department, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. · Department of Oncology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. · Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA. ·Curr Med Chem · Pubmed #23992308.

ABSTRACT: Indometacin, an inhibitor of cyclooxygenase-2 (COX-2), has been shown to exert anticancer effects in a variety of cancers. However, the effect and mechanism of indometacin on high glucose (HG)-induced proliferation and invasion of pancreatic cancer (PC) cells remain unclear. Multiple lines of evidence suggest that a large portion of pancreatic cancer (PC) patients suffer from either diabetes or HG which contributing PC progression. In this study, we report that indometacin down-regulated HG-induced proliferation and invasion via up-regulating E-cadherin but not COX-2 in PC cells. Additionally, the E-cadherin transcriptional repressors, Snail and Slug, were also involved in the process. Furthermore, the proliferation and invasion of PC cells, incubated in HG medium and treated with indometacin were significantly increased when E-cadherin was knocked down (Si-E-cad). Moreover, the protein levels of MMP-2, MMP-9, and VEGF were increased in PC cells transfected with Si-E-cad. Finally, the activation of the PI3K/AKT/GSK-3β signaling pathway was demonstrated to be involved in indometacin reversing HG-induced cell proliferation and invasion in PC cells. In conclusion, these results suggest that indometacin plays a key role in down-regulating HG-induced proliferation and invasion in PC cells. Our findings indicate that indometacin could be used as a novel therapeutic strategy to treat PC patients who simultaneously suffer from diabetes or HG.

25 Article Resveratrol inhibits the epithelial-mesenchymal transition of pancreatic cancer cells via suppression of the PI-3K/Akt/NF-κB pathway. 2013

Li, Wei / Ma, Jiguang / Ma, Qingyong / Li, Bin / Han, Liang / Liu, Jiangbo / Xu, Qinhong / Duan, Wanxing / Yu, Shuo / Wang, Fengfei / Wu, Erxi. ·Department of Hepatobiliary Surgery, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. · Department of Oncology, First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China. · Department of Pharmaceutical Sciences, North Dakota State University, Fargo, ND 58105, USA. ·Curr Med Chem · Pubmed #23992306.

ABSTRACT: Resveratrol (trans-3,4',5-trihydroxystilbene), a natural polyphenolic compound detected in grapes, berries, and peanuts, possesses a wide spectrum of pharmacological properties, including anti-tumor metastasis activities. However, the underlying mechanisms through which resveratrol inhibits the metastasis of pancreatic cancer are still not fully elucidated. As epithelial-to-mesenchymal transition (EMT) is a key player for metastasis in tumor, the aim of this study is to determine whether resveratrol affects EMT in pancreatic cancer cells and the related mechanism. The results showed that resveratrol not only inhibited cell proliferation, migration, and invasion in a dose-dependent manner, but also mediated the expression of EMT-related genes (E-cadherin, N-cadherin, vimentin, MMP-2, and MMP-9) which are important for cancer cellular motility, invasiveness and metastasis during tumorigenesis. In addition, the levels of phospho-Akt and phospho- NF-κB in BxPC-3 and Panc-1 cells were reduced by both resveratrol and LY294002 (a PI3-K inhibitor). Furthermore, transforming growth factor-β (TGF-β)-induced alterations in cell morphology that are characteristic of EMT as well as increased cell invasive ability could also be reversed by resveratrol. Taken together, these data indicate that resveratrol suppresses pancreatic cancer migration and invasion through the inhibition of the PI-3K/Akt/NF-κB signaling pathway. This study suggests that resveratrol may be a potential anticancer agent for pancreatic cancer.

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