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

Wu, Xiaoqing
Tang, Wenhua
Marquez, Rebecca T.
Li, Ke
Highfill, Chad Allen
He, Fengtian
Lian, Jiqin
Lin, Jiayuh
Fuchs, James R.
Ji, Min
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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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Date
2016-02-12
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Impact Journals
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Keywords
Chemo/radio-resistance, pSTAT3, Pancreatic cancer, lip-FLLL32, CSCs
Citation
Wu, X., Tang, W., Marquez, R. T., Li, K., Highfill, C. A., He, F., … Xu, L. (2016). Overcoming chemo/radio-resistance of pancreatic cancer by inhibiting STAT3 signaling. Oncotarget, 7(10), 11708–11723. http://doi.org/10.18632/oncotarget.7336
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