Journal
ONCOTARGET
Volume 7, Issue 10, Pages 11708-11723Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.7336
Keywords
chemo/radio-resistance; pSTAT3; pancreatic cancer; lip-FLLL32; CSCs
Categories
Funding
- National Institutes of Health [R01 CA178831, CA191785]
- Kansas Bioscience Authority Rising Star Award
- University of Kansas Bold Aspiration Strategic Initiative Award
- China National Basic Research Program [2015CB553702]
- National Science and Technology Major Project [2015ZX09501-009]
- [K-INBRE P20 GM103418]
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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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