The Important Role of Survivin in KRAS-driven Pancreatic Cancer

Other Titles


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.

Journal / Series

Volume & Issue


202 pages


Date Issued




Exosome; Extracellular Vesicle; KRAS; Pancreatic Cancer; Survivin


Effective Date

Expiration Date




Union Local


Number of Workers

Committee Chair

Cerione, Richard A.

Committee Co-Chair

Committee Member

Lin, Hening
Baird, Barbara A.

Degree Discipline

Chemistry and Chemical Biology

Degree Name

Ph. D., Chemistry and Chemical Biology

Degree Level

Doctor of Philosophy

Related Version

Related DOI

Related To

Related Part

Based on Related Item

Has Other Format(s)

Part of Related Item

Related To

Related Publication(s)

Link(s) to Related Publication(s)


Link(s) to Reference(s)

Previously Published As

Government Document




Other Identifiers


Attribution-NonCommercial-NoDerivatives 4.0 International


dissertation or thesis

Accessibility Feature

Accessibility Hazard

Accessibility Summary

Link(s) to Catalog Record