Abstract 4508: Penfluridol-induced endoplasmic reticulum stress leads to autophagy-mediated pancreatic tumor growth suppression

Abstract

Abstract Pancreatic cancer is the fourth leading cause of cancer-related deaths in the United States. Experimental and clinical evidences suggested that high basal state autophagy in pancreatic tumors could induce resistance to chemotherapies. Recently, we have demonstrated that penfluridol suppresses pancreatic tumor growth by autophagy-mediated apoptosis both in vitro and in vivo. (Ranjan and Srivastava, Scientific Reports: 2016;6:26165; PMID: 27189859), however the mechanism of autophagy induction by penfluridol was not clear. Several studies have established that endoplasmic reticulum (ER) stress could lead to autophagy and inhibit tumor progression. In the current study, we demonstrated that penfluridol induced ER stress in BxPC-3, AsPC-1 and Panc-1, pancreatic cancer cell lines as indicated by up regulation of ER stress markers such as BIP, CHOP and IRE1α after treatment with penfluridol in a concentration-dependent manner. Inhibiting ER stress by pre-treatment with pharmacological inhibitors such as sodium phenylbutyrate and mithramycin or by silencing CHOP using CHOPsiRNA, blocked penfluridol-induced autophagy. These results clearly indicated that penfluridol induced ER stress lead to autophagy in our model. Western blot analysis of subcutaneously implanted AsPC-1 and BxPC-3 tumors as well as orthotopically implanted Panc-1 tumors demonstrated upregulation of BIP, CHOP and IRE1α expression in the tumors lysates from penfluridol treated mice as compared to tumors from control mice. Altogether, our study established that penfluridol induced ER stress mediated autophagy in pancreatic tumor. Our study opened a new therapeutic target for advanced chemotherapies against pancreatic cancer. (Supported in part by RO1 grant CA129038, awarded by National Cancer Institute, NIH). Citation Format: Alok Ranjan, Sharavan Ramachandran, Nehal Gupta, Sanjay Srivastava. Penfluridol-induced endoplasmic reticulum stress leads to autophagy-mediated pancreatic tumor growth suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4508. doi:10.1158/1538-7445.AM2017-4508