TY - JOUR
T1 - Mesothelioma cancer cells are glutamine addicted and glutamine restriction reduces YAP1 signaling to attenuate tumor formation
AU - Adhikary, Gautam
AU - Shrestha, Suruchi
AU - Naselsky, Warren
AU - Newland, John J.
AU - Chen, Xi
AU - Xu, Wen
AU - Emadi, Ashkan
AU - Friedberg, Joseph S.
AU - Eckert, Richard L.
N1 - Publisher Copyright:
© 2022 Wiley Periodicals LLC.
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
KW - GLS
KW - SLC1A5
KW - glutamine addiction
KW - glutamine depletion therapy
KW - mesothelioma
KW - Cell Proliferation
KW - Humans
KW - Minor Histocompatibility Antigens/genetics
KW - Transcription Factors/genetics
KW - Amino Acid Transport System ASC/genetics
KW - Adaptor Proteins, Signal Transducing/genetics
KW - YAP-Signaling Proteins
KW - Glutamine/metabolism
KW - Mesothelioma/genetics
KW - Cell Line, Tumor
KW - Mesothelioma, Malignant
UR - http://www.scopus.com/inward/record.url?scp=85145057182&partnerID=8YFLogxK
U2 - 10.1002/mc.23497
DO - 10.1002/mc.23497
M3 - Article
C2 - 36562471
AN - SCOPUS:85145057182
SN - 0899-1987
VL - 62
SP - 438
EP - 449
JO - Molecular Carcinogenesis
JF - Molecular Carcinogenesis
IS - 4
ER -