Date on Master's Thesis/Doctoral Dissertation
Pharmacology and Toxicology
Pharmacology and Toxicology, PhD
Paraoxonase 2; N-(3-oxododecanoyl)-l-homoserine lactone; lung cancer; lung adenocarcinoma; mitochondria; metabolomics
Paraoxonase 2 (PON2) is an intracellular, multifunctional enzyme with near-ubiquitous tissue distribution. Within cells, PON2 is localized to mitochondria and endoplasmic reticulum (ER), where it mitigates the formation of reactive oxygen species (ROS). PON2’s chief enzymatic function is its lactonase activity, through which it catalyzes the hydrolysis of a bacterial quorum-sensing molecule, N-(3-oxododecanoyl)-l-homoserine lactone (C12), effectively disrupting bacterial intercellular communication and protecting against infection. C12 is produced by the opportunistic pathogen Pseudomonas aeruginosa and has been shown to disrupt various aspects of eukaryotic host cell physiology and evoke apoptotic cell death through the activity of PON2. Additionally, PON2 has garnered growing attention for its potential role in human cancers. Recent research has demonstrated that PON2 confers apoptotic resistance to tumor cells in vitro and is upregulated in a variety of solid and hematologic cancers. However, the detailed mechanisms by which PON2 facilitates these phenotypes remains unclear. The following dissertation explores PON2’s influence on airway mitochondrial physiology in response to C12, lung tumor cell metabolism, and in vivo lung tumorigenesis. Herein, we demonstrate that below a cytotoxic threshold, C12 disrupts mitochondrial metabolism and network morphology to hinder the cell proliferation of murine tracheal epithelial cells in a PON2-dependent manner. Furthermore, we show that loss of PON2 expression selectively impairs lung adenocarcinoma cell proliferation by exacerbating the production of ROS and compromising cellular bioenergetics. Finally, we examined PON2’s role in lung tumorigenesis in vivo using a variety of implanted and spontaneous tumor models to show that PON2 plays a limited role in murine lung tumor development. Taken together, these findings highlight PON2’s diverse roles in the context of pulmonary physiology.
Whitt, Aaron, "The roles of PON2 in mitochondrial physiology, lung tumor cell proliferation, and lung tumorigenesis." (2022). Electronic Theses and Dissertations. Paper 3847.
Retrieved from https://ir.library.louisville.edu/etd/3847