Abstract 4794: An undesired effect of chemotherapy: gemcitabine promotes pancreatic cancer cell invasiveness through upregulation of CXCR4.

Abstract

Abstract Pancreatic cancer (PC) remains a therapeutic challenge with a rising incidence and unabated mortality. Gemcitabine (GEM), the current standard of care drug, is largely ineffective due to chemoresistance, thus underscoring the need for a refined understanding of the molecular mechanisms that drive drug-resistant nature of this malignancy. Recently, we have shown that CXCL12/CXCR4 signaling axis is involved in conferring chemoresistance to PC cells. Here, we explored the effect of GEM on this resistance mechanism and its functional consequences. Our data demonstrated that GEM upregulated CXCR4 expression in two PC cell lines (MiaPaCa and Colo357) in a dose- and time- dependent manner. GEM-induced CXCR4 expression was dependent on generation of reactive oxygen species (ROS) as it was abrogated upon pre-treatment of PC cells with radical scavenger N-acetyl-L-cysteine (NAC). CXCR4 upregulation by GEM correlated with time-dependent accumulation of p65/NF-κB and HIF-1α in the nucleus. An enhanced binding of p65/NF-κB and HIF-1α to the CXCR4 promoter was observed in chromatin immunoprecipitation assay in GEM-treated PC cells, while their silencing by RNA interference suppressed GEM-induced CXCR4 expression. ROS induction upon GEM treatment preceded the nuclear accumulation of p65/NF-κB and HIF-1α and suppression of ROS diminished these effects. Effect of ROS on p65/NF-κB and HIF-1α was mediated through activation of ERK1/2 and Akt and their pharmacological inhibition also suppressed GEM-induced CXCR4 upregulation. Lastly, our data demonstrated that GEM-treated PC cells were more motile and exhibited significantly greater invasiveness against a CXCL12 gradient. Altogether, these findings reinforces the role of CXCL12/CXCR4 signaling in GEM resistance and point toward an undesired effect of chemotherapy that is potentiation of invasion and spread of resistant tumor cells. Citation Format: Sumit Arora, Arun Bhardwaj, Seema Singh, Sanjeev K. Srivastava, Steven McClellan, William E. Grizzle, Laurie B. Owen, Ajay P. Singh. An undesired effect of chemotherapy: gemcitabine promotes pancreatic cancer cell invasiveness through upregulation of CXCR4. [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 4794. doi:10.1158/1538-7445.AM2013-4794