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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 ... show 2 more
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