A wealth of experimental evidence clearly connects the regulation of cellular metabolism with the development of cancer. Metabolic changes undergone by cancer cells are now considered a key event in the transition from a normal cell to a cancer cell. In particular, those changes that cause a cancer cell to rely on aerobic glycolysis for ATP production, as opposed to mitochondrial oxidative phosphorylation (OXPHOS), appear to be important drivers of the cancer phenotype. Glioblastoma multiforme (GBM) is characterized as being an exceptionally glycolytic cancer. There are no current effective therapies for GBM, and GBM patient mortality is high. Therefore, mechanisms driving the glycolytic switch in cancer cells may be promising targets of novel, effective anti-cancer therapeutics for GBM. In a screen to identify genes that regulate metabolism in cancer cells, protein tyrosine phosphatase, mitochondrial 1 (PTPMT1) was found to push cells towards a cancer metabolic program by inhibiting OXPHOS. PTPMT1 was further found to be highly expressed in cells from GBM patients. The studies outlined in this proposal are designed to fully characterize protein tyrosine phosphatase, mitochondrial 1 (PTPMT1) as a novel molecule regulating metabolic programs in normal and cancer cells. By altering PTPMT1 levels and activity in normal and cancer cells, Aim 1 of this proposal will determine the mechanism of PTPMT1 action by identifying targets of phospho-regulation, as well as physical interacting partners, and how these interactions affect normal and cancer cell metabolic programs.
Aim 2 will establish PTPMT1 as a regulator of OXPHOS metabolic programs in GBM cells and tumors. Reducing PTPMT1 levels and activity is expected to reprogram cancer metabolism to that of a normal cell, with opposite effects expected for increased levels and activity of PTPMT1. PTPTM1 is expected to regulate OXPHOS by interacting with and reducing the activity of specific components of the electron transport chain.
Much knowledge has been generated in the past decades regarding the causes of cancer;yet cancer remains a lethal disease, highlighting the critical need for new, more effective anticancer therapeutics. Cancer cells almost universally undergo a change in metabolism that drives their ability to rapidly proliferate. The research proposed in thi application presents a strategy to characterize a gene that regulates cancer cell metabolism and which is highly expressed in glioblastoma cells, and may therefore provide a promising new anticancer target.
|Lanning, Nathan J; Looyenga, Brendan D; Kauffman, Audra L et al. (2014) A mitochondrial RNAi screen defines cellular bioenergetic determinants and identifies an adenylate kinase as a key regulator of ATP levels. Cell Rep 7:907-17|