Date on Master's Thesis/Doctoral Dissertation

5-2017

Document Type

Doctoral Dissertation

Degree Name

Ph. D.

Department

Pharmacology and Toxicology

Degree Program

Pharmacology and Toxicology, PhD

Committee Chair

Li, Chi

Committee Co-Chair (if applicable)

Siskind, Leah

Committee Member

Siskind, Leah

Committee Member

Eaton, John

Committee Member

Mitchell, Robert

Committee Member

Mitchell, Thomas

Author's Keywords

cancer; cell death; cell proliferation; homoserine lactones; pon2

Abstract

Pseudomonas aeruginosa produces N-(3-oxododecanoyl)-homoserine lactone (C12) as a quorum-sensing molecule that functions to facilitate bacteria-bacteria communication. C12 has also been reported to affect many aspects of human host cell physiology, including evoking cell death in various types of cells. However, the signaling pathway(s) leading to C12-triggerred cell death remains unclear. To clarify cell death signaling induced by C12, we examined mouse embryonic fibroblasts (MEFs) deficient in one or more caspases. Our data indicate that, unlike most apoptotic inducers, C12 evokes a novel form of apoptosis in cells, probably through the direct induction of mitochondrial membrane permeabilization. Importantly, C12 induces apoptosis in human tumor cells and inhibits tumor growth in animals independent of both pro- and anti-apoptotic Bcl-2 proteins. Previous studies indicate that C12 requires the lactonase/arylesterase paraoxonase 2 (PON2) to exert its cytotoxicity on MEFs. PON2 is known to function as a lactonase to cleave C12. We found that PON2 was overexpressed in tissues from non-small cell lung carcinoma (NSCLC) patients and oncogenically transformed human bronchia/tracheal epithelial (NHBE) cells. Reducing PON2 expression in NSCLC cell lines as well as several non-transformed cell lines rendered them resistant to C12. However, PON2 expression is only important for the proliferation of NSCLC cells but not that of their untransformed counterparts, indicating that PON2 mediates apoptosis independently of its function to modulate cell proliferation. Overall, our results reveal a unique mitochondrial apoptotic signaling pathway triggered by C12/PON2 interaction and PON2 plays distinct roles in apoptosis signaling and cell proliferation.

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