Inhibition of cellular glutamate efflux as a novel strategy to curb canine hemangiosarcoma proliferation and survival

Viary, Janice

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https://hdl.handle.net/2142/124543 Copy

Description

Title

Inhibition of cellular glutamate efflux as a novel strategy to curb canine hemangiosarcoma proliferation and survival

Author(s)

Viary, Janice

Issue Date

2024-05-01

Director of Research (if dissertation) or Advisor (if thesis)

Fan, Timothy M

Committee Member(s)

• Schnelle, Amy N
• Samuelson, Jonathan P

Department of Study

Vet Clinical Medicine

Discipline

VMS-Veterinary Clinical Medcne

Degree Granting Institution

University of Illinois at Urbana-Champaign

Degree Name

M.S.

Degree Level

Thesis

Keyword(s)

• canine hemangiosarcoma
• cancer metabolism
• glutamine metabolism
• glutamate signaling
• riluzole
• sulfasalazine

Abstract

Canine hemangiosarcoma (cHSA) is a common and highly aggressive tumor, originating from either malignant endothelial cells or bone marrow pluripotent cells. Cytoreduction, typically involving surgery (splenectomy) and cytotoxic drugs (doxorubicin), have been the mainstay treatment for splenic cHSA. However, therapeutic benefits are short-lived due to the limited effectiveness of chemotherapy and proliferative capacity of cHSA cells. Despite these interventions, pet dogs will eventually succumb to the disease due to distant metastasis or fatal hemorrhages. Efforts to enhance outcomes for cHSA have primarily focused on improving cytoreduction strategies. An alternative approach that hasn’t been widely explored involves targeting metabolic vulnerabilities to exert cytostatic effects, which could potentially maintain a better quality of life and extend survival times. Altered metabolism is considered one of the hallmarks of cancer, and one of its components is the dysregulation of glutamine metabolism. Despite being a nonessential amino acid for normal cells, cancer cells exhibit a heightened dependence on glutamine, a phenomenon commonly referred to as “glutamine addiction”. Since these tumor cells consume glutamine at high rates, depriving them of this amino acid often triggers senescence and eventual cell death. Glutamine plays multiple vital roles in cell function—it contributes to protein synthesis, provides nitrogen for the synthesis of nonessential amino acids, purines, pyrimidines, and hexosamines, and acts as a source of glutamate for glutathione synthesis. These functions support the rapid growth and proliferation of cancer cells, emphasizing the significance of glutamine in cancer metabolism. The dependence of cancer cells on glutamine metabolism presents as an opportunity for potential therapeutic interventions. Numerous studies have investigated inhibitors of various components of cellular glutamine-associated machinery, including glutamate receptors, enzymes, and transporters, with the goal of reducing extracellular glutamate excretion and/or inhibiting subsequent glutamate signaling. Significantly, metabotropic glutamate receptor 1 (mGluR1) inhibition strategies in melanoma and breast cancer have shown promising findings in suppressing cancer growth, underscoring the importance and vulnerability of glutamate signaling in cancer cells. Dysregulation of glutamate transporters also produces excessive extracellular glutamate, which activates mGluRs on cancer cells and allows for autocrine and paracrine signaling, contributing to rapid cellular proliferation and survival. Overall, there is substantial scientific evidence supporting the targeting of extracellular glutamate excretion and mGluR signaling as potential strategies to curb growth and progression of various cancers. Given this evidence, this study seeks to evaluate the disruption of cellular glutamate trafficking on cHSA cells. Specifically, we aimed to inhibit extracellular glutamate excretion by repurposing existing FDA-approved drugs, riluzole and sulfasalazine. Riluzole and sulfasalazine are commercially available drugs that disrupt cellular glutamate trafficking by inhibiting glutamate exocytosis and xCT-mediated transport, respectively. We hypothesize that the disruptive effects of riluzole and sulfasalazine would attenuate extracellular shuttling of cytosolic glutamate and consequent signaling mediated through mGluR1/5 on cHSA cell lines, effectively curbing their proliferation and survival.

Graduation Semester

2024-05

Type of Resource

Thesis

Copyright and License Information

Copyright 2024 Janice Viary

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