title: Overcoming chemo/radio-resistance of pancreatic cancer by inhibiting STAT3 signaling.
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.
authors.affiliation: 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.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Wenhua
authors.initials: W
authors.lastname: Tang
authors.affiliation: Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA.
authors.forename: Rebecca T
authors.initials: RT
authors.lastname: Marquez
authors.affiliation: Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Departments of Molecular Biosciences and Radiation Oncology, University of Kansas, Lawrence, KS, USA.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Highfill
authors.affiliation: 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.|Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing, China.
authors.forename: Fengtian
authors.initials: F
authors.lastname: He
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Biochemistry and Molecular Biology, Third Military Medical University, Chongqing, China.
authors.forename: Jiqin
authors.initials: J
authors.lastname: Lian
authors.affiliation: Department of Pediatrics, College of Medicine, Ohio State University, Columbus, OH, USA.
authors.forename: Jiayuh
authors.initials: J
authors.lastname: Lin
authors.affiliation: Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, Ohio State University, Columbus, OH, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Fuchs
authors.affiliation: School of Chemistry and Chemical Engineering, Southeast University, Nanjing, Jiangsu, China.
authors.forename: Min
authors.initials: M
authors.lastname: Ji
authors.affiliation: Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI, USA.|Department of Cell Biology and Cell Engineering Research Centre, State Key Laboratory of Cancer Biology, Fourth Military Medical University, Xi'an, Shanxi, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D003474:Curcumin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D011836:Radiation Tolerance; D011897:Random Allocation; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D016019:Survival Analysis; D000093542:Gemcitabine
chemical_list: C548902:FLLL 32; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D003841:Deoxycytidine; D003474:Curcumin; D000093542:Gemcitabine
keywords: CSCs; chemo/radio-resistance; lip-FLLL32; pSTAT3; pancreatic cancer