Modulation of host cell translation and metabolism by Kaposi's sarcoma-associated herpesvirus Public Deposited

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  • March 22, 2019
Creator
  • Bhatt, Aadra
    • Affiliation: School of Medicine, Department of Microbiology and Immunology
Abstract
  • Kaposi sarcoma-associated herpesvirus (KSHV) causes Kaposi sarcoma, multicentric Castleman's disease and primary effusion lymphoma (PEL), an aggressive subtype of B cell non-Hodgkin lymphoma (B-NHL). The lack of a vaccine, and poorly tolerated standard treatments are the onus for devising efficacious therapeutics for KSHV-associated malignancies. Several KSHV proteins deregulate cell signaling, creating a favorable environment for viral persistence, with cancer being a casualty for the host cell. Thus, understanding how KSHV, an obligate intracellular parasite, manipulates host cell processes may reveal avenues for therapeutic intervention for these cancers. The interplay between KSHV and the host PI3K/AKT/mTOR signaling pathway forms the common theme of this dissertation. This signaling pathway regulates diverse cellular processes; among them are apoptosis, proliferation and metabolism. KSHV encodes several proteins that manipulate this pathway, which is highly active in latently infected cells, thus underscoring the importance of PI3K/AKT/mTOR signaling for the virus. Therefore, we first examined the relative contribution of each arm of this pathway in latently infected PEL cells. We found that compared to single inhibitors, dual inhibitors of PI3K/AKT/mTOR kinases were significantly more effective at inhibiting PEL proliferation in both in vitro and preclinical in vivo models. Dual inhibitors also potently diminished autocrine and paracrine proliferative loops, further demonstrating their broad efficacy. PI3K/AKT/mTOR kinases are essential regulators of cellular anabolic and catabolic processes. However, the metabolic sequelae of hyperactive signaling in B-NHL were largely unknown. Using metabolomics, we found that two metabolic pathways, glycolysis and fatty acid synthesis, were upregulated in latently infected PEL cells. Enhanced glycolysis was found to be essential for generating intermediates for fatty acid synthesis. The lipid biosynthetic enzyme fatty acid synthase is aberrantly expressed in PEL. FASN inhibition induces apoptosis in PEL, and further, sensitizes PEL to PI3K/AKT/mTOR inhibitors, highlighting the utility of developing FASN as a therapeutic target. We discovered that the KSHV viral protein kinase (vPK) activates PI3K/AKT/mTOR signaling by phosphorylating the downstream effector ribosomal S6 protein, a critical player in protein translation. Furthermore, vPK expression imparts resistance to PI3K/AKT/mTOR pathway inhibitors, and determining the extent and mechanism of resistance is a future goal of this study.
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  • In Copyright
Advisor
  • Damania, Blossom
Degree
  • Doctor of Philosophy
Graduation year
  • 2013
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