Overcoming chemo/radio-resistance of pancreatic cancer by inhibiting STAT3 signaling

// Xiaoqing Wu 1, 2, 3 , Wenhua Tang 1, 2 , Rebecca T. Marquez 1 , Ke Li 1 , Chad A. Highfill 1 , Fengtian He 1, 2, 4 , Jiqin Lian 2, 4 , Jiayuh Lin 5 , James R. Fuchs 6 , Min Ji 3 , Ling Li 2, 7 , Liang Xu 1, 2 1 Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA 2 Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA 3 School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu, China 4 Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing, China 5 Department of Pediatrics, College of Medicine, Ohio State University, Columbus, OH, USA 6 Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, OH, USA 7 Department of Cell Biology and Cell Engineering Research Centre, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi’an, Shanxi, China Correspondence to: Liang Xu, e-mail: xul@ku.edu Ling Li, e-mail: liling25@fmmu.edu.cn Keywords: chemo/radio-resistance, pSTAT3, pancreatic cancer, lip-FLLL32, CSCs Received: September 22, 2015 Accepted: January 23, 2016 Published: February 12, 2016 ABSTRACT Chemo/radio-therapy resistance to the deadly pancreatic cancer is mainly due to the failure to kill pancreatic cancer stem cells (CSCs). Signal transducer and activator of transcription 3 (STAT3) is activated in pancreatic CSCs and, therefore, may be a valid target for overcoming therapeutic resistance. Here we investigated the potential of STAT3 inhibition in sensitizing pancreatic cancer to chemo/radio-therapy. We found that the levels of nuclear pSTAT3 in pancreatic cancer correlated with advanced tumor grade and poor patient outcome. Liposomal delivery of a STAT3 inhibitor FLLL32 (Lip-FLLL32) inhibited STAT3 phosphorylation and STAT3 target genes in pancreatic cancer cells and tumors. Consequently, Lip-FLLL32 suppressed pancreatic cancer cell growth, and exhibited synergetic effects with gemcitabine and radiation treatment in vitro and in vivo . Furthermore, Lip-FLLL32 reduced ALDH1-positive CSC population and modulated several potential stem cell markers. These results demonstrate that Lip-FLLL32 suppresses pancreatic tumor growth and sensitizes pancreatic cancer cells to radiotherapy through inhibition of CSCs in a STAT3-dependent manner. By targeting pancreatic CSCs, Lip-FLLL32 provides a novel strategy for pancreatic cancer therapy via overcoming radioresistance.