Abstract 982: Malate dehydrogenase 2 confers resistance to docetaxel chemotherapy in prostate cancer through JNK pathway

Abstract

Abstract Resistance to chemotherapy represents a significant obstacle in cancer therapeutics. Novel mechanistic understandings in cancer cell chemotherapeutic sensitivity and resistance can optimize treatment and improve patient outcome. Molecular alterations in the metabolic pathways are associated with cancer development; however, the role of these alterations in chemotherapy efficacy is largely unknown. In this study, we identified a novel role for mitochondrial malate dehydrogenase 2 (MDH2) in mediating prostate cancer resistance to docetaxel-chemotherapy. We performed gene expression microarray analyses on frozen needle biopsies from prostate cancer patients before they underwent neoadjuvant chemotherapy. We observed that genes in the metabolic pathways are significantly altered in the cancer epithelium versus the matched- tumor adjacent benign epithelium. In addition, some of the metabolic gene expression alterations are associated with the long-term treatment outcome. Patients with MDH2 overexpression in cancer cells had a significantly lower relapse-free survival (RFS) based on the Kaplan-Meier analysis. To investigate the underlying mechanism responsible for this clinical observation, we found that MDH2 expression was elevated in prostate cancer cell lines compared to benign prostate epithelial cells. Then we established stable MDH2 knock-down prostate cancer lines and evaluated cell proliferation and cell viability within the context of chemotherapy. We found that MDH2 knockdown significantly enhanced the docetaxel sensitivity in prostate cancer cell lines LNCaP, C42B and PC3. Metabolic and redox measurement showed that MDH2 knockdown significantly reduced cellular ATP levels and increased the ADP/ATP and NAD+/NADH level. In addition, MDH2 knockdown significantly increased reactive oxygen specifies (ROS) while maintaining the oxygen consumption rate. These metabolic alterations were associated with the sustained activation of JNK signaling cascade after docetaxel treatment and the inactivation of apoptosis inhibitor BCL2. Taken together, these data suggest a novel function for MDH2 in prostate cancer development and chemotherapy, in which the cancer associated metabolic and redox alteration confers resistance to chemotherapy by regulating pathways of signal transduction and cell death. 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 982. doi:1538-7445.AM2012-982