Résumé
Prostate cancer (PCa) is one of the leading causes of death from cancer in men. High Gleason grade PCa are characterized by aggressive tumors with poorly differentiated cells and a high metastatic potential. They are often refractory to chemical castration but still treated with hormone therapy to which docetaxel or cabazitaxel are added when they become resistant to the anti-androgen. Despite many clinical trials with other chemotherapeutic agents, response rates remain low pointing towards the need for new alternative therapies. Using an in silico approach based on a 86 genes signature which could distinguish between low-grade and high-grade tumors, we identified 9 genes (PCCB, SHMT2, DPM1, RHOT2, RPL13, CD59, EIF4AI, CDKN2C, JUN) for which expression levels across the NCI-60 cell lines panel was significantly correlated (p< 0.05) to oxaliplatin but not to cisplatin sensitivity. Among them, SHMT2 which is overexpressed in high grade PCa, encodes the mitochondrial isoform of serine hydroxymethyl transferase, which converts glycine to serine, which is then exported to the cytoplasm to generate the one-carbon units that are required for the biosynthesis of purines. SiRNA-mediated donwregulation of SHMT2 in DU145 or LNCaP prostate tumor cell lines rendered cells resistant to oxaliplatin but not to cisplatin. CHO 51-11 cells which express a catalytically inactive SHMT2 were also resistant to oxaliplatin but not to cisplatin as compared to CHO K1 control cells. The selective resistance to oxaliplatin was not due to the oxalate moiety since addition of oxalate to cisplatin could not restore the level of sensitivity of CHO cells to oxaliplatin. Selectivity could however be attributed to the diamino cyclohexane (DACH) moiety of oxaliplatin since CHO 51-11 cells were also resistant to dichloro(1,2-diaminocyclohexane)-platinum(II). Resistance to oxaliplatin could also be achieved by SHMT1 downregulation (the cytoplasmic form of SHMT) or by an alteration of the pool of glycine and serine. SHMTs can indirectly regulate the methylation status of DNA, and we showed that siRNA-mediated downregulation of SHMTs in hypomethylated LNCaP cells increased the global level of DNA methylation, as measured by 4 CpGs methylation status of LINE-1. Interestingly, increased level of global methylation status was associated with increased resistance to oxaliplatin. Altogether, our results identified oxaliplatin as a potential alternative for the treatment of high grade prostate cancers and SHMT2 (and SHMT1) as selective markers of oxaliplatin sensitivity which involves, at least in part, the regulation of global levels of DNA methylation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2665. doi:1538-7445.AM2012-2665