Inactivation of Pancreatic Stellate Cells by Exendin-4 Inhibits the Migration and Invasion of Pancreatic Cancer Cells

Meizhu Yan1 ,* Manru Shen1 ,* Linfang Xu1 ,* Jiying Huang,1 Guijun He,1 Min An,1 Xiaocui Li,1 Zhenjun Gao,1 Xin Meng2 1Department of Gastroenterology, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai 201700, People’s Republic of China; 2Department of Hospital Infection Management, Zhongshan Hospital Qingpu Branch, Fudan University, Shanghai 201700, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhenjun GaoDepartment of Gastroenterology, Zhongshan Hospital Qingpu Branch, Fudan University, 1158 East Gongyuan Road, Shanghai 201700, People’s Republic of ChinaEmail prom_doc@163.comXin MengDepartment of Hospital Infection Management, Zhongshan Hospital Qingpu Branch, Fudan University, 1158 East Gongyuan Road, Shanghai 201700, People’s Republic of ChinaTel +86-21-69719190-5515Email qphospital_mx@126.comBackground: Pancreatic stellate cells (PSCs) are precursor cells of cancer-associated fibroblasts that promote tumor proliferation, invasion, and metastasis. The glucagon-like peptide-1 receptor agonist exendin-4 has been reported to exhibit anticancer effects against several tumor cells; however, the function and mechanism underlying the effects of exendin-4 on pancreatic cancer cells remain unclear.Methods: Gene expression levels were determined using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot assay. Cell viability, migration and invasion were assessed using the cell counting kit-8 (CCK-8), wound healing, and transwell assays, respectively. A xenografted tumor model was established in mouse to evaluate the effects of exendin-4 in vivo.Results: Exendin-4 treatment led to the inactivation of PSCs and suppressed their proliferation and migration. Moreover, we also found that exendin-4 attenuated NF-κB-dependent SDF-1 secretion. Furthermore, pancreatic cancer cells incubated with conditioned medium obtained from exendin-4-treated PSCs showed a decreased ability to proliferate, migrate, and invade as compared to the control cells, which is similar to the effects induced by the CXCR4 inhibitor, AMD3100. Consistent with in vitro results, we also confirmed that exendin-4 indirectly targeted pancreatic cancer cells in vivo by attenuating the function of PSCs and suppressing the deposition of extracellular matrix.Conclusion: These results revealed that exendin-4-treated PSCs could suppress pancreatic cancer cell proliferation and invasion, offering a potential strategy for the treatment of pancreatic cancer.Keywords: pancreatic cancer, pancreatic stellate cells, exendin-4, SDF-1