Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer with a poor prognosis that is characterized by marked chemoresistance to a broad spectrum of chemotherapeutic drugs, as a consequence of intrinsic cell-autonomous factors, and extrinsic stroma-associated factors. Dual specificity protein phosphatase 1 (DUSP1) has been reported to be overexpressed in pancreatic cancer cells in PDAC. Moreover, DUSP1 was shown to be essential for efficient in vitro colony formation and in vivo tumorigenicity, indicating that DUSP1 may contribute to the biological aggressiveness of PDAC. However, it is not known whether DUSP1 overexpression contributes to PDAC chemoresistance. Using BxPC3 and COLO-357 human pancreatic cancer cells, we show that gemcitabine activated c-JUN N-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38 MAPK), key kinases in two major stress-activated signaling pathways. Activation of JNK and p38 MAPK was associated with increased apoptosis, as evidenced by increased cleavage of PARP and Caspase 3. However, gemcitabine also enhanced DUSP1 transcription, as demonstrated by increased DUSP1 mRNA levels, and increased RNA polymerase II loading at both DUSP1 promoter and gene body. Moreover, shRNA-mediated inhibition of DUSP1 enhanced JNK and p38 MAPK activation and sensitized both cell lines to gemcitabine. Taken together, these results suggest that gemcitabine-mediated upregulation of DUSP1 contributes to a negative feedback loop that attenuates its beneficial actions on stress pathways and apoptosis, raising the possibility that targeting DUSP1 in PDAC may have the dual advantage of suppressing proliferation while enhancing gemcitabine chemosensitivity.
Citation Format: Fang Liu, Murray Korc. DUSP1 is a novel target for enhancing pancreatic cancer cell sensitivity to gemcitabine. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2951. doi:10.1158/1538-7445.AM2013-2951
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