Metformin May Function As An Anti-Cancer Agent Of Pancreatic Cancer Via Targeting Ret Signaling Pathway

Pancreatic cancer (PaCA) is one of the most lethal human cancers and is the fourth leading cause of cancer-related deaths in the United States. However, there are currently no established recommendations for prevention of PaCA using pharmacological agents. Metformin has recently gained attention as an anti-cancer drug and/or a chemoprevention agent because of its effects on inhibiting mTOR, lowering hyperinsulinemia, modulating inflammatory responses, and selectively killing cancer stem cells. However, the key underlying molecular mechanisms for the inhibitory effects of metformin on PaCA progression remain largely unknown. Using RNA sequencing followed by the confirmation of RT-PCR and Western blotting, we found that metformin significantly decreased the mRNA and protein levels of RET (REarranged during Transfection), a single-pass transmembrane receptor tyrosine kinase (RTK). RET and its ligand, glial cell-derived neurotrophic factor (GDNF), were strongly expressed in PaCA and correlated to invasion and worse survival after surgical resection. GDNF, as a chemoattractant for PaCA cells, can activate RET to induce tumor progression, migration and invasion in vitro and in vivo. We further observed that metformin significantly inhibited GDNF-induced migration and invasion of PANC-1 cells. These data indicate that targeting RET with metformin or the combination of metformin and RET inhibitors may be an attractive and novel strategy for the prevention and treatment of PaCA progression and metastasis. To elucidate the molecular mechanisms for the inhibitory effects of metformin on the growth and spread of PaCA in humans, further in vitro and in vivo studies are warranted to investigate how metformin modulates RET signaling to inhibit the progression and metastasis of PaCA. Such studies have potential clinical significance using metformin as adjuvant preventive and therapeutic options for PaCA prevention and treatment. [This work was supported by grants from the National Cancer Institute at the National Institutes of Health (K07CA190541 and P30CA072720) and the National Natural Science Foundation of China (Grant No.: 81470132)] Citation Format: Xiang-Lin Tan, Wen Yue, Tao Wang, Darren Carpizo, Yong Lin, Xi Zheng, Chung S. Yang, Lanjing Zhang, Qing Xu, Robert S. DiPaola. Metformin may function as an anti-cancer agent of pancreatic cancer via targeting RET signaling pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1796.