Abstract 3045: Novel altered mitochondrial genes in prostate cancer progression

Abstract

Abstract Introduction: Prostate cancer (PCa) is the most prevalent cancer amongst men and the second most common cause of cancer related-deaths in the US. Although PCa has a long latent period of development, clinically, the disease has very heterogeneous phenotypes ranging from indolent asymptomatic cases to very aggressive metastatic life threatening and lethal forms. The most critical clinical challenge in the management of the patients is identifying those individuals at risk of developing aggressive metastatic disease. Our long term objective is to identify the molecules and characterize the mechanisms that are involved in aggressive PCa. Some of the most significant hallmarks of aggressive disease include disabled apoptosis, invasion/ metastasis, and oxidative stress, and these are directly or indirectly linked to deregulated mitochondria. We hypothesized that deregulated mitochondria and mitochondria associated genes could serve as surrogates for prostate cancer disease stratification and potentially as useful prognostic and diagnostic biomarkers. Understanding the mechanism and roles of mitochondria associated genes in the progression of PCa will potentially better discriminate the more aggressive forms and provide better treatment and clinical management opportunities of the disease. Methods: We have compared the gene expression profiles of 168 genes that are involved in the biogenesis, function and energy metabolism of mitochondria and those that are involved in mitochondria energy metabolism using quantitative real time PCR arrays on disease stratified cell lines derived from individual patients and matched prostatectomy tissues with different malignancy phenotypes. Validations of differentially expressed genes have been done by Western blot, siRNA knockdowns, proliferation and invasion assays, IHC and IFA. Results: A total of 48 genes are significantly upregulated (p ≤ 0.05) in prostate cancer cases and 2 are significantly downregulated (p ≤ 0.05). UCP2, the most significantly upregulated gene with a fold change of 10.57 is involved in uncoupling oxidative phosphorylation. We demonstrate novel correlations between the expression of multiple mitochondria associated genes with aggressive PCa. These were validated by Western blot, confocal microscopy, IHC and metabolite efflux assays. siRNA knockdown of specific mitochondria associated genes suppress malignant transformation and the invasive and migratory capacity of PCa cells. Conclusions: We have identified mitochondria genes that are differentially expressed in PCa cells lines and prostatectomy tissues with different malignancy phenotypes. These findings are currently being validated using disease stratified TMAs. Further studies are focusing on uncovering the mechanisms responsible for progression and metastasis of PCa that are modulated by mitochondria associated genes. These could assist in the development of novel diagnostic and therapeutic strategies for the disease. Citation Format: Tanya C. Burch, J S. Rhim, Julius O. Nyalwidhe. Novel altered mitochondrial genes in prostate cancer progression. [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 3045. doi:10.1158/1538-7445.AM2015-3045