Mesothelioma cancer cells are glutamine addicted and glutamine restriction reduces YAP1 signaling to attenuate tumor formation

Gautam Adhikary, Suruchi Shrestha, Warren Naselsky, John J. Newland, Xi Chen, Wen Xu, Ashkan Emadi, Joseph S. Friedberg, Richard L. Eckert

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Glutamine addiction is an important phenotype displayed in some types of cancer. In these cells, glutamine depletion results in a marked reduction in the aggressive cancer phenotype. Mesothelioma is an extremely aggressive disease that lacks effective therapy. In this study, we show that mesothelioma tumors are glutamine addicted suggesting that glutamine depletion may be a potential therapeutic strategy. We show that glutamine restriction, by removing glutamine from the medium or treatment with inhibitors that attenuate glutamine uptake (V-9302) or conversion to glutamate (CB-839), markedly reduces mesothelioma cell proliferation, spheroid formation, invasion, and migration. Inhibition of the SLC1A5 glutamine importer, by knockout or treatment with V-9302, an SLC1A5 inhibitor, also markedly reduces mesothelioma cell tumor growth. A relationship between glutamine utilization and YAP1/TEAD signaling has been demonstrated in other tumor types, and the YAP1/TEAD signaling cascade is active in mesothelioma cells and drives cell survival and proliferation. We therefore assessed the impact of glutamine depletion on YAP1/TEAD signaling. We show that glutamine restriction, SLC1A5 knockdown/knockout, or treatment with V-9302 or CB-839, reduces YAP1 level, YAP1/TEAD-dependent transcription, and YAP1/TEAD target protein (e.g., CTGF, cyclin D1, COL1A2, COL3A1, etc.) levels. These changes are observed in both cells and tumors. These findings indicate that mesothelioma is a glutamine addicted cancer, show that glutamine depletion attenuates YAP1/TEAD signaling and tumor growth, and suggest that glutamine restriction may be useful as a mesothelioma treatment strategy.

Original languageEnglish
Pages (from-to)438-449
Number of pages12
JournalMolecular Carcinogenesis
Volume62
Issue number4
DOIs
StatePublished - Mar 2023

Keywords

  • GLS
  • SLC1A5
  • glutamine addiction
  • glutamine depletion therapy
  • mesothelioma
  • Cell Proliferation
  • Humans
  • Minor Histocompatibility Antigens/genetics
  • Transcription Factors/genetics
  • Amino Acid Transport System ASC/genetics
  • Adaptor Proteins, Signal Transducing/genetics
  • YAP-Signaling Proteins
  • Glutamine/metabolism
  • Mesothelioma/genetics
  • Cell Line, Tumor
  • Mesothelioma, Malignant

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