Abstract 2939: Induction of apoptosis in prostate cancer cells by altering cell metabolism

Abstract

Abstract The levels of ceramides, sphingosine and their related metabolites have been reported to play an important role in cell fate by determining the balance between apoptosis and cell survival signaling through what has been called the sphingolipid rheostat. One of sphingosine metabolic product, sphingosine-1-phosphate, has been widely proven to be related with tumor growth, resistance to apoptosis, angiogenesis, metastasis and invasiveness in several tumors. In prostate cancer, sphingosine-1-phosphate levels correlate with risk of progression to castration-resistant prostate cancer (CRPC), PSA levels, Gleason score, positive surgical margins, lymph node extension, metastatic extension and mortality. Hypoxia-inducible factors (HIFs) act as pleiotropic transcription factors which serve as major components for cancer progression, upregulation of HIFs are essential for metastasis and tumor growth once hypoxia has ensued. Several relations between HIFs and ceramides/sphingosine metabolism have been reported recently, suggesting that both mechanisms might be somehow interconnected. Despite decades of research inhibitors to HIF have been few and far between. The DNA-intercalating agent doxorubicin was identified one such inhibitor by a mechanism not yet understood. The major mechanism of doxorubicin-mediated apoptosis has been established to be induced by the transcription factor, p53. The p53 cell cycle arrest is usually through p21 which has been shown to have enhanced expression in response to sphingosine kinase 2, one of the enzymes that mediate the conversion of sphingosine to sphingosine-1-phosphate. Several studies associating chemotherapy with different drugs that attempt to modify sphingosine and ceramides metabolism have been published with some remarkable results, although never complete responses. We hypothesize that the incomplete responses may be due to an incomplete blockade of the conversion of ceramides and sphingosine towards their phosphorylated metabolites, sphingosine-1-phosphate and ceramide-1-phospate respectively. Previous work has focused on single agents to enhance chemotherapy. In this work we are interested in studying the combination of different modifiers in the metabolism of ceramides/sphingosine with doxorubicin in order to achieve a total metabolic blockade in an effort to elicit a complete clinical response for prostate cancer. Citation Format: Gonzalo Torga, Steven Mooney, Jelani C. Zarif, Kenneth J. Pienta. Induction of apoptosis in prostate cancer cells by altering cell metabolism. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2939. doi:10.1158/1538-7445.AM2015-2939