Date of Award

Spring 5-3-2024

Level of Access Assigned by Author

Open-Access Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Biomedical Sciences

Advisor

Calvin P. H. Vary

Second Committee Member

Michaela R. Reagan

Third Committee Member

Thomas Gridley

Additional Committee Members

Benjamin King

Robert Koza

Lucy Liaw

Abstract

Multiple myeloma (MM) is an incurable cancer of plasma cells with a 5-year survival rate of 60%. Obesity correlates with increased incidence of MM and high body mass index correlates with a poor treatment response. Studies of obesity and myeloma are mainly at the epidemiological level and have not extensively explored the molecular mechanisms of this relationship. Therefore, there is a critical need to understand how obesity contributes to support cancers such as MM. The intersection of obesity and MM and the largely understudied role of fatty acid (FA) metabolism in MM cells motivated the immediate goals of this work: to identify the molecular components of FA metabolism that contribute to MM cell survival and proliferation and understand the mechanisms of how those components contribute MM cell fitness. To help combat MM cell drug resistance, the ultimate goal of this research is to identify novel therapeutic targets in MM cells and possibly other hematological malignancies. To achieve our goals, we used bioinformatic approaches to first identify candidate FA metabolism genes and molecular phenotyping and unbiased transcriptomic and proteomic approaches to understand the mechanisms of the phenotypes that were observed. An in vitro system of human cell lines of both MM and acute myeloid leukemia and of human bone marrow adipocytes differentiated from human mesenchymal stem cells was used. This body of work provides evidence that the acyl-CoA synthetase long chain family members (ACSLs) support MM cell mitochondrial function, survival, and proliferation. The ACSL family convert free long-chain fatty acids into fatty acyl-CoA esters and play key roles in catabolic and anabolic fatty acid metabolism. Here, we show that inhibition of ACSLs in human myeloma cell lines using the pharmacological inhibitor Triascin C (TriC) causes apoptosis and decreases proliferation in a dose- and time-dependent manner, induces a transcriptome associated with the integrated stress response and cell death, a proteomic and functional profile associated with mitochondrial dysfunction. This work demonstrates that targeting the ACSL family in MM cells holds promise as a novel therapeutic target and warrants additional mechanistic studies to understand how the ACSL family MM cells respond to terminal stressors.

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