Abstract
Abstract Colon cancer is the second most common cause of cancer-related deaths. Many patients present with colon cancer in advanced stages of metastasis, where the outcome is poor and mortality is high. Invasion is an essential capability acquired by cancer cells to metastasize to distant organs. Currently there are no effective strategies to prevent invasion because the underlying mechanisms are poorly understood. During early development of colon cancer, cyclooxygenase 2 (COX-2) is constitutively induced. We have shown that COX-2 promotes invasion by disrupting cell adhesion and increasing motility in HCA-7 colon cancer cells that constitutively express endogenous COX-2. To further determine the mechanisms by which COX-2 stimulates motility and to confirm this cellular behavior in other colon epithelial cells, we established HCT-15 colon cancer cells that stably express recombinant COX-2 (HCT-15-COX-2). Scratch wound gap assays were used to monitor cell motility and proliferation in HCA-7 and HCT-15-COX-2 cells. HT-29 colon cancer cells that do not express COX-2 and parental HCT-15 cells were used as controls. HCA-7 and HCT-15-COX-2 cells closed the gap significantly faster than HT-29 and HCT-15 cells. Inhibition of COX-2 in HCA-7 and HCT-15-COX-2 cells by the COX-2 selective inhibitor NS-398 decreased the gap closing. Interestingly, the enhanced gap closing ability of HCA-7 and HCT-15-COX-2 cells correlated with activation of ERKs, mitogen-activated protein kinases that are known to mediate COX-2 signaling to stimulate colon cancer cell growth. Activation of ERK depended on COX-2 activity. Inhibition of ERK signaling in HCA-7 and HCT-15-COX-2 cells reduced gap closing as effectively as NS-398. Furthermore, inhibition of ERK signaling prevented migration of both HCA-7 and HCT-15-COX-2 cells in modified Boyden chamber assays. Interestingly, reduced migration by inhibition of ERK signaling correlated with increased protein levels of adherens junction protein alpha-catenin. Our data reveal for the first time a role for ERK to promote cell migration in response to COX-2 signaling in addition to its stimulation of cancer cell growth. Since cardiovascular toxicity caused by long-term use of COX-2 inhibitors raises several concerns, targeting ERK can be an alternative approach for preventing colon cancer growth and invasion. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5214.
Published Version
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