Type

Text

Type

Dissertation

Advisor

Chan, Chia-Hsin (Lori) | Lin, Richard Z | Frohman, Michael A | Girnun, Geoffrey D | Haley, John

Date

2017-12-01

Keywords

Oncology | aerobic | Molecular biology | cancer | Biochemistry | glycolysis | Kras | pancreas | Pik3ca

Department

Department of Molecular and Cellular Pharmacology

Language

en_US

Source

This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.

Identifier

http://hdl.handle.net/11401/78279

Publisher

The Graduate School, Stony Brook University: Stony Brook, NY.

Format

application/pdf

Abstract

Pancreatic ductal adenocarcinoma is the 3rd leading cause of cancer-related death with a <5% five-year survival rate. We previously demonstrated that PI3K p110? (gene name Pik3ca) is required for oncogenic Kras to initiate pancreatic tumors in mice. To study the role of Pik3ca in pancreatic tumors after they are formed, we employed CRISPR/Cas9 to delete Pik3ca in cultured cancer cells derived from the Kras(G12D/+);Pdx1Cre (KC) pancreatic tumor mouse model. Silencing Pik3ca impaired cell proliferation and invasion, as well as decreased glycolysis and oxidative phosphorylation. Pharmacologic inhibition of p110? using BYL719 showed similar results. Orthotopic implantation of KC cell lines in the pancreas of C57BL/6 mice showed that Pik3ca deletion decreased tumor growth resulting in significantly increased median survival (parental 28 days vs. Pik3ca-null 94.5 days). Pik3ca-null KC cells exhibit decreased PGC1? expression and these cellular phenotypes were all reversed by PGC1? overexpression. To study the requirement of Pik3ca in a spontaneous pancreatic tumor mouse model, we produced mice with pancreata harboring the KrasG12D mutation that express a tetracycline-regulated Pik3ca transgene but lacking endogenous Pik3ca alleles. Turning off transgenic Pik3ca decreased PGC1? expression. In summary, our findings indicate that p110? supports invasive growth of pancreatic tumors by regulating the expression of PGC1?. | 100 pages

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