Semester

Fall

Date of Graduation

2022

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Biochemistry

Committee Chair

Werner Geldenhuys

Committee Co-Chair

Elena Pugacheva

Committee Member

Elena Pugacheva

Committee Member

Aaron Robart

Committee Member

Mike Ruppert

Committee Member

Scott Weed

Abstract

Non-Small Cell Lung Cancer (NSCLC) is a pulmonary malignancy most commonly associated with smoking, or exposure to asbestos or Radon. Approximately, 1.6 Million deaths occur each year due to lung cancer. Lung Cancer is categorized by two main types, Small Cell Lung Cancer (SCLC) and NSCLC. NSCLC accounts for approximately 85% of all lung cancer cases and is subdivided into three sub-categories: Adenocarcinoma, the most common and leading cause of death in the United States; Squamous Cell Carcinoma (SCC), and Large Cell Carcinoma. Though NSCLC treatment regimens have shown increasing clinical benefit over the last two decades with targeted therapies. Emergence of resistance still remains a clinical obstacle. Endoplasmic reticulum oxidoreductase-1α (ERO1α) is a flavin adenosine dinucleotide (FAD) containing enzyme (flavoenzyme) that has been shown to be a poor prognostic indicator in multiple cancer types. ERO1α is responsible for folding secretory and transmembrane proteins through disulfide bond formation in conjunction with protein disulfide isomerase (PDI). However, ERO1α has also been shown to form de novo disulfide bridges. ERO1α contributes directly to protein folding through redox reactions that occur between the reactive cysteine bridges (Cys-94-Cys99, and Cys394-Cys397) within ERO1α by which electrons are shuttled from PDI onto ERO1α at Cys94-Cys99, then shuttled onto Cys394-Cys397, followed by transfer of electrons on the FAD ring at which time Molecular oxygen is used as a terminal electron acceptor to produce hydrogen peroxide. Hydrogen peroxide can then be eliminated by peroxidases and other enzymes to reduce ER stress. Proper protein folding is required to maintain homeostasis within the endoplasmic reticulum. Here, we identify ERO1α as novel target for targeted therapy in NSCLC and propose ERO1α clonogenicity and tumorigenecity through oxidative folding of LAMC2.

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