The Important Role of Survivin in KRAS-driven Pancreatic Cancer

Abstract

Pancreatic cancer is a highly aggressive and deadly type of cancer, and effective strategies to treat the disease are lacking. In general, a vast majority of patients have a point mutation in KRAS that results in its constitutive activation. Since most efforts to target this protein have failed, there is a need to better understand how KRAS mediates its effects, with the hope that this information will lead to the development of novel approaches to treat pancreatic cancer patients. In my thesis, I first described that the expression of mutant KRAS in pancreatic cancer cells can generate exosomes, a subtype of extracellular vesicles (EVs), which are enriched in a cell survival protein, Survivin. The exosomes were shown to promote the survival of cells cultured under nutrient-deficient conditions. They also conferred drug resistance to the cells that were treated with paclitaxel, or a novel therapy for pancreatic cancer which combines an ERK inhibitor and an autophagy inhibitor. Furthermore, I also discovered that Survivin is capable of stabilizing the expression of the proto-oncogene and transcription factor, MYC. This effect is due to the ability of Survivin to prevent the dephosphorylation at serine 62 of MYC from protein phosphatase 2A (PP2A). Since enhanced MYC expression in pancreatic cancer cells increases cell proliferation and survival, this result suggests an important role of Survivin in driving pancreatic cancer progression. Interestingly, I also demonstrated that the expression of Survivin increases glycolysis in pancreatic cancer cells. Based on the metabolomic analysis performed on cells depleted of Survivin expression using the inhibitor YM155, I identified that Survivin could be key to regulating the isomerization between dihydroxyacetone phosphate (DHAP) and glyceraldehyde 3-phosphate (G3P) mediated by triosephosphate isomerase (TPI). These findings highlight how mutant forms of KRAS increase Survivin expression to promote several processes that are important for cellular transformation, and they implicate that approaches which include targeting Survivin could be used as an effective strategy to treat pancreatic cancer.