The Warburg effect is a famous cancer-related phenomenon which describes a metabolic shift from oxidative phosphorylation to glycolysis and fermentation in a cancer cell. Many studies suggest that the Warburg effect is in response to changes (mutation, deletion, and depletion) within the mitochondrial genome. We previously showed that poorly differentiated prostate cancer cells have reduced mitochondrial genome content and are more influenced by the Warburg effect than well differentiated prostate cancer cells. The reduction of mitochondrial genome content induced overexpression and activation of proto-oncogenic Ras, which is responsible for the activation of AKT and ERK, leading to advanced phenotypes of prostate cancer. Farnesylation (membrane localization) of Ras was required for Ras activation and was induced by the overexpression of 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGR), the rate-limiting enzyme of the mevalonate pathway, through inhibition of hypoxia-dependent degradation of HMGR. We hypothesize that increased intracellular oxygen concentration due to the Warburg effect responding to the reduction of mitochondrial genome content determines membrane localization of Ras via induction of farnesylation mediated by overexpression of HMGR. In the poorly differentiated prostate cancer cells such as LNCaP (intracellularly normoxic cells), Ras localized in both the plasma membrane and Golgi, whereas in well differentiated prostate cancer cells such as PC-3 (intracellularly hypoxic cells), Ras is prominent in the cytosol. Exogenous hypoxic conditions eliminated Ras localization in the membrane in PC-3, possibly through inhibition of the farnesylation of Ras. In contrast, exogenous hyperoxic condition increased membrane localization of Ras in LNCaP. Next, we demonstrated the localization of other prenylated proteins, such as Rab5a and prelamin A. In the PC-3, Rab5a and prelamin A were localized in the early endosomes and the nuclear membrane, respectively. In LNCaP, they were present throughout the cytosol and inside of the nucleus. Similar to Ras, the localization of Rab5a and prelamin A was reversible with changes in exogenous oxygen concentration. Our results revealed a coherent mechanism that directly links changes in intracellular oxygen concentration, determined by the mitochondrial genome, with the progression of prostate cancer.

Citation Format: Ara Kim, Masahiro Higuchi. Warburg effect increases intracellular oxygen concentration and determines membrane localization of Ras and other prenylated proteins. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1694. doi:10.1158/1538-7445.AM2013-1694