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

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/TEADdependent 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.

Targeted Therapy in Mesotheliomas: Uphill All the Way

“…YAP1 levels and YAP1/TEAD target proteins can be decreased by limiting glutamine. V-9302 (an inhibitor of SLC1A5-dependent glutamine uptake) or CB-839, which inhibits the GLS-catalyzed conversion of glutamine to glutamate, has been developed for this purpose and demonstrated activity in MM cell lines [ 98 ]. Thus, limiting glutamine/glutamate could be an effective and viable treatment option for mesothelioma.…”

Monitoring and modelling the glutamine metabolic pathway: a review and future perspectives

“…The Warburg effect, observed in tumor cells, involves the conversion of glycolytic pyruvate to lactate instead of further catabolism through the TCA cycle, leading to reduced energy production per mole of glucose (Manoj et al, 2022 ; Warburg, 1956 ). Glutaminolysis serves as an alternative energy source in tumor cells, and its acceleration has been observed in glutamine-addicted cancers such as highly invasive ovarian and mesothelioma cancers (Adhikary et al, 2022 ; Medina, 2001 ; Li & Le, 2018 ; Yang et al, 2017a ). However, the role of glutamine in continuous cell proliferation as an anabolic substrate is controversial, as its limited availability in tissues and circulation restricts its biological role in this process (Brosnan, 2003 ; Lacey & Wilmore, 1990 ).…”