Targeting mitochondrial glutaminase activity inhibits oncogenic transformation

By Jian‐bin Wang, J. Erickson, R. Fuji, Sekar Ramachandran, Ping Gao, Ramani Dinavahi, K. Wilson, A. Ambrosio, S. M. Dias, C. V. Dang and 1 more. Cancer Cell, 2010

824 citations recorded by the source corpus.

SUMMARY Rho GTPases impact a number of activities important for oncogenesis. Here we describe a small molecule inhibitor which blocks oncogenic transformation induced by various Rho GTPases in fibroblasts, and the growth of human breast cancer and B lymphoma cells, without affecting normal cells. We identify the target of this inhibitor to be the metabolic enzyme glutaminase, which catalyzes the hydrolysis of glutamine to glutamate. We show that transformed fibroblasts and breast cancer cells exhibit elevated glutaminase activity that is dependent on Rho GTPases and NFκB activity, and is blocked by the small molecule inhibitor. These findings highlight a previously unappreciated connection between Rho GTPase activation and cellular metabolism, and demonstrate that targeting glutaminase activity can inhibit oncogenic transformation.

Subfields: Biochemistry, Cancer Research, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/44f96ac764c23fba1fd8c0fcc83301d3a1b144b2

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Citations in the corpus

MYC, metabolism, cell growth, and tumorigenesis. (2013, background): “Two studies showed that inhibitors of glutaminase, compound 968 and BPTES, also inhibited growth of MYC-induced tumor xenografts (Wang et al. 2010; Le et al. 2012).”
Glutaminolysis and Transferrin Regulate Ferroptosis (2015, background): “Compound 968 (968), an inhibitor of GLS (Wang et al., 2010), significantly inhibited serum-dependent necrosis (Figure 5B).”
From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy (2016, neutral): “BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
MYC, Metabolism, and Cancer. (2015, background): “Pharmacologic inhibition of GLS has also been documented to curb tumor progression of an inducible MYC-driven human lymphoma xenograft model in a cellautonomous fashion (212, 213).”
Reprogramming of glucose, fatty acid and amino acid metabolism for cancer progression (2015, background): “One specific GLS inhibitor, the small molecule 968, blocks the GLS activity and inhibits oncogenic transformation in preclinical models of cancer, without affecting normal cells [161].”
Glutaminolysis activates Rag-mTORC1 signaling. (2012, background): “Inhibition of GLS prevents oncogenic transformation and slows cell growth in certain types of gliomas (Seltzer et al., 2010; Wang et al., 2010).”
Glutamine oxidation maintains the TCA cycle and cell survival during impaired mitochondrial pyruvate transport (2014, background): “GLS and transaminases are required for growth of glutamine-addicted cells (Cheng et al., 2011; Gao et al., 2009; Qing et al., 2012; Wang et al., 2010).”
Targeting cancer metabolism: a therapeutic window opens (2011, background): “These different functions of GLS1 and GLS2 are likely to have key roles in cancer metabolism, and the growth of transformed cells can be selectively inhibited by targeting glutaminase activit”
Antitumor Activity of the Glutaminase Inhibitor CB-839 in Triple-Negative Breast Cancer (2014, background): “A critical step in the utilization of glutamine is its conversion to glutamate by the mitochondrial enzyme glutaminase (5, 6).”
Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism (2018, background): “Glutamine is initially hydrolyzed via the enzyme glutaminase (GLS) (Wang et al., 2010) to produce glutamate, which is used in protein synthesis and generation of glutathione to regulate reactive oxygen”