An undesired effect of chemotherapy: gemcitabine promotes pancreatic cancer cell invasiveness through reactive oxygen species-dependent, nuclear factor κB- and hypoxia-inducible factor 1α-mediated up-regulation of CXCR4.

Authors:
Sumit Arora
Sumit Arora
Mitchell Cancer Institute
Mobile | United States
Arun Bhardwaj
Arun Bhardwaj
Mitchell Cancer Institute
Mobile | United States
Seema Singh
Seema Singh
Mitchell Cancer Institute
Mobile | United States
Dr. Sanjeev K Srivastava, PhD
Dr. Sanjeev K Srivastava, PhD
Mitchell Cancer Institute
Instructor
Cancer Biologist
Mobile, AL | United States
Steven McClellan
Steven McClellan
University of South Alabama
United States
Chaitanya S Nirodi
Chaitanya S Nirodi
Mitchell Cancer Institute
Gary A Piazza
Gary A Piazza
Mitchell Cancer Institute
William E Grizzle
William E Grizzle
University of Alabama at Birmingham
Birmingham | United States

J Biol Chem 2013 Jul 5;288(29):21197-207. Epub 2013 Jun 5.

Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604, USA.

Recently, we have shown that CXCL12/CXCR4 signaling plays an important role in gemcitabine resistance of pancreatic cancer (PC) cells. Here, we explored the effect of gemcitabine on this resistance mechanism. Our data demonstrate that gemcitabine induces CXCR4 expression in two PC cell lines (MiaPaCa and Colo357) in a dose- and time-dependent manner. Gemcitabine-induced CXCR4 expression is dependent on reactive oxygen species (ROS) generation because it is abrogated by pretreatment of PC cells with the free radical scavenger N-acetyl-L-cysteine. CXCR4 up-regulation by gemcitabine correlates with time-dependent accumulation of NF-κB and HIF-1α in the nucleus. Enhanced binding of NF-κB and HIF-1α to the CXCR4 promoter is observed in gemcitabine-treated PC cells, whereas their silencing by RNA interference causes suppression of gemcitabine-induced CXCR4 expression. ROS induction upon gemcitabine treatment precedes the nuclear accumulation of NF-κB and HIF-1α, and suppression of ROS diminishes these effects. The effect of ROS on NF-κB and HIF-1α is mediated through activation of ERK1/2 and Akt, and their pharmacological inhibition also suppresses gemcitabine-induced CXCR4 up-regulation. Interestingly, our data demonstrate that nuclear accumulation of NF-κB results from phosphorylation-induced degradation of IκBα, whereas HIF-1α up-regulation is NF-κB-dependent. Lastly, our data demonstrate that gemcitabine-treated PC cells are more motile and exhibit significantly greater invasiveness against a CXCL12 gradient. Together, these findings reinforce the role of CXCL12/CXCR4 signaling in gemcitabine resistance and point toward an unintended and undesired effect of chemotherapy.

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July 2013
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