Non-Essential Amino Acid Availability Influences Proteostasis and Breast Cancer Cell Survival During Proteotoxic Stress

Author:

Sannino Sara1ORCID,Manuel Allison M.23ORCID,Shang Chaowei1ORCID,Wendell Stacy G.24ORCID,Wipf Peter5ORCID,Brodsky Jeffrey L.1ORCID

Affiliation:

1. 1Department of Biological Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania.

2. 2Health Sciences Mass Spectrometry Core, University of Pittsburgh, Pittsburgh, Pennsylvania.

3. 3Mass Spectrometry and Proteomics Core, The University of Utah, Salt Lake City, Utah.

4. 4Department of Pharmacology and Chemical Biology University of Pittsburgh, Pittsburgh, Pennsylvania.

5. 5Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania.

Abstract

Abstract Protein homeostasis (proteostasis) regulates tumor growth and proliferation when cells are exposed to proteotoxic stress, such as during treatment with certain chemotherapeutics. Consequently, cancer cells depend to a greater extent on stress signaling, and require the integrated stress response (ISR), amino acid metabolism, and efficient protein folding and degradation pathways to survive. To define how these interconnected pathways are wired when cancer cells are challenged with proteotoxic stress, we investigated how amino acid abundance influences cell survival when Hsp70, a master proteostasis regulator, is inhibited. We previously demonstrated that cancer cells exposed to a specific Hsp70 inhibitor induce the ISR via the action of two sensors, GCN2 and PERK, in stress-resistant and sensitive cells, respectively. In resistant cells, the induction of GCN2 and autophagy supported resistant cell survival, yet the mechanism by which these events were induced remained unclear. We now report that amino acid availability reconfigures the proteostasis network. Amino acid supplementation, and in particular arginine addition, triggered cancer cell death by blocking autophagy. Consistent with the importance of amino acid availability, which when limited activates GCN2, resistant cancer cells succumbed when challenged with a potentiator for another amino acid sensor, mTORC1, in conjunction with Hsp70 inhibition. Implications: These data position amino acid abundance, GCN2, mTORC1, and autophagy as integrated therapeutic targets whose coordinated modulation regulates the survival of proteotoxic-resistant breast cancer cells.

Funder

National Institute of General Medical Sciences

Office of Research Infrastructure Programs, National Institutes of Health

Medical Center, University of Pittsburgh

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology,Molecular Biology

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