%0 Journal Article
%T RASSF1A and the Taxol Response in Ovarian Cancer
%A Susannah Kassler
%A Howard Donninger
%A Michael J. Birrer
%A Geoffrey J. Clark
%J Molecular Biology International
%D 2012
%I Hindawi Publishing Corporation
%R 10.1155/2012/263267
%X The RASSF1A tumor suppressor gene is frequently inactivated by promoter methylation in human tumors. The RASSF1A protein forms an endogenous complex with tubulin and promotes the stabilization of microtubules. Loss of RASSF1A expression sensitizes cells to microtubule destabilizing stimuli. We have observed a strong correlation between the loss of RASSF1A expression and the development of Taxol resistance in primary ovarian cancer samples. Thus, we sought to determine if RASSF1A levels could dictate the response to Taxol and whether an epigenetic therapy approach might be able to reverse the Taxol resistant phenotype of RASSF1A negative ovarian tumor cells. We found that knocking down RASSF1A expression in an ovarian cancer cell line inhibited Taxol-mediated apoptosis and promoted cell survival during Taxol treatment. Moreover, using a combination of small molecule inhibitors of DNA Methyl Transferase enzymes, we were able restore RASSF1A expression and Taxol sensitivity. This identifies a role for RASSF1A in modulating the tumor response to Taxol and provides proof of principal for the use of epigenetic therapy to overcome Taxol resistance. 1. Introduction RASSF1A is a poorly understood tumor suppressor that can modulate the cell cycle, tubulin dynamics and apoptosis [1¨C3]. It is subjected to epigenetic inactivation at high frequency in a broad range of human tumors, including approximately 50% of ovarian tumors [1, 4, 5]. Overexpression of RASSF1A promotes hyperstabilization of microtubules reminiscent of Taxol [6, 7], and previous investigations have shown that loss of RASSF1A sensitizes cells to microtubule destabilizing drugs such as nocodazole [7]. Thus, RASSF1A appears to play an important role in modulating microtubule stabilization. This implies that the RASSF1A levels in a tumor cell may impact how the cell responds to Taxol treatment. The development of resistance to Taxol remains a serious problem in the treatment of ovarian cancer. The most frequent mechanism by which RASSF1A is inactivated in tumors is by hypermethylation promoter leading to transcriptional silencing [1, 4, 5]. Thus, the gene remains intact, just dormant. Over recent years, a series of small molecules have been identified that can inhibit the DNA methylation system and restore expression of genes that have suffered aberrant promoter methylation [8]. This has given rise to the concept of epigenetic therapy, whereby a tumor would be treated with drugs to restore the expression and function of RASSF1A or some other epigenetically inactivated target. If RASSF1A plays a key
%U http://www.hindawi.com/journals/mbi/2012/263267/