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Oncotarget. 2016 Mar 8;7(10):11708-23. doi: 10.18632/oncotarget.7336.

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

Wu X1,2,3, Tang W1,2, Marquez RT1, Li K1, Highfill CA1, He F1,2,4, Lian J2,4, Lin J5, Fuchs JR6, Ji M3, Li L2,7, Xu L1,2.

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Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA.
Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.
School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu, China.
Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing, China.
Department of Pediatrics, College of Medicine, Ohio State University, Columbus, OH, USA.
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, OH, USA.
Department of Cell Biology and Cell Engineering Research Centre, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shanxi, China.


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.


CSCs; chemo/radio-resistance; lip-FLLL32; pSTAT3; pancreatic cancer

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