Research Papers:
Overcoming chemo/radio-resistance of pancreatic cancer by inhibiting STAT3 signaling
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Abstract
Xiaoqing Wu1,2,3, Wenhua Tang1,2, Rebecca T. Marquez1, Ke Li1, Chad A. Highfill1, Fengtian He1,2,4, Jiqin Lian2,4, Jiayuh Lin5, James R. Fuchs6, Min Ji3, Ling Li2,7, Liang Xu1,2
1Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA
2Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA
3School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu, China
4Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing, China
5Department of Pediatrics, College of Medicine, Ohio State University, Columbus, OH, USA
6Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, OH, USA
7Department 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: [email protected]
Ling Li, e-mail: [email protected]
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.
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