title: Desmoplasia suppression by metformin-mediated AMPK activation inhibits pancreatic cancer progression.
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.
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Wanxing
authors: W
authors: Duan
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Ke
authors: K
authors: Chen
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Zhengdong
authors: Z
authors: Jiang
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Xin
authors: X
authors: Chen
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Liankang
authors: L
authors: Sun
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Jiahui
authors: J
authors: Li
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Jianjun
authors: J
authors: Lei
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Qinhong
authors: Q
authors: Xu
authors: Department of Anesthesiology, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Jiguang
authors: J
authors: Ma
authors: Department of General Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Xuqi
authors: X
authors: Li
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Liang
authors: L
authors: Han
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Zheng
authors: Z
authors: Wang
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Zheng
authors: Z
authors: Wu
authors: Department of Neurosurgery, Baylor Scott & White Health, Temple 76508, TX, USA.
authors: Fengfei
authors: F
authors: Wang
authors: 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.
authors: Erxi
authors: E
authors: Wu
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China. Electronic address: qyma56@mail.xjtu.edu.cn.
authors: Qingyong
authors: Q
authors: Ma
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital, Xi'an Jiaotong University, Xi'an 710061, China.
authors: Zhenhua
authors: Z
authors: Ma
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D018450:Disease Progression; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000494:pharmacology*; D005260:Female; D005355:Fibrosis; D006801:Humans; D008687:Metformin / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D019899:Paracrine Communication / Q000187:drug effects; D010766:Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D016207:Cytokines; D020536:Enzyme Activators; D003841:Deoxycytidine; D008687:Metformin; D055372:AMP-Activated Protein Kinases; D000093542:Gemcitabine
keywords: AMP-activated protein kinase (AMPK); Desmoplastic reaction; Metformin; Pancreatic cancer; Pancreatic stellate cells (PSCs)