All ETDs from UAB

Advisory Committee Chair

Sooryanarayana Varambally

Advisory Committee Members

Douglas Hurst

Mick D Edmonds

Upender Manne

Bin Ren

Document Type

Dissertation

Date of Award

2021

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Cancer is a complex disease characterized by uncontrolled growth of transformed cells that can arise in many tissue types throughout the body (e.g., breast, lung, prostate, pancreas, lymph nodes) and is a major cause of death worldwide. Cancer progression resulting in aggressive or metastatic disease accounts for one of the leading causes of death worldwide, second only to heart disease in the US. Incidentally, cancer-related mortality has been on a steady decline, dropping 25% over the last 25 years [1]. This could be attributed to improved and earlier diagnoses and better treatment options being developed over the past few decades. Molecular profiling, transcriptome sequencing and data integration from many high-throughput platforms unraveled dysregulation in many metabolic pathways in cancer. Since cancer cells are fast-growing, their metabolic needs are enhanced, hence the requirement for de novo synthesis of essential metabolites. One critical requirement of fast-growing cells and a historically important pathway in cancer is the nucleotide biosynthetic pathway and its enzymes are valuable targets for small molecule inhibition. Hanahan and Weinberg have proposed other characteristics, collectively called hallmarks of cancer [2], based on extensive research. Hallmarks that we have sought to target with these studies are cell proliferation, invasion, and deregulated cellular energetics. We embarked on data analysis and identification of targets that are involved in de novo purine biosynthesis as well as those involved in cancer metastasis. The work presented in this thesis discusses research in the areas of de novo purine biosynthesis, describing the role of methylenetetrahydrofolate dehydrogenase (NADP+ Dependent) 1-like (MTHFD1L), an enzyme involved in nucleotide metabolism, overexpressed in breast cancer, as well as, describing the expression and role of a collagen modifying enzyme prolyl 4-hydroxylase subunit alpha 1 (P4HA1) in lung adenocarcinoma. We found P4HA1 to play an oncogenic role in lung adenocarcinoma. Knockdown of expression resulting in significantly reduced cell proliferation, colony formation, and invasion. Likewise, with MTHFD1L, in the context of breast cancer, we found reduced cell proliferation and invasion upon knockdown of expression. Overall, this thesis describes two potential therapeutic targets that are amenable to small molecule inhibition.

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