Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis
Yan Xiang, … , Dean W. Felsher, Chi V. Dang
Yan Xiang, … , Dean W. Felsher, Chi V. Dang
Published April 27, 2015
Citation Information: J Clin Invest. 2015;125(6):2293-2306. https://doi.org/10.1172/JCI75836.
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Research Article Oncology

Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis

Abstract

Glutaminase (GLS), which converts glutamine to glutamate, plays a key role in cancer cell metabolism, growth, and proliferation. GLS is being explored as a cancer therapeutic target, but whether GLS inhibitors affect cancer cell–autonomous growth or the host microenvironment or have off-target effects is unknown. Here, we report that loss of one copy of Gls blunted tumor progression in an immune-competent MYC-mediated mouse model of hepatocellular carcinoma. Compared with results in untreated animals with MYC-induced hepatocellular carcinoma, administration of the GLS-specific inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) prolonged survival without any apparent toxicities. BPTES also inhibited growth of a MYC-dependent human B cell lymphoma cell line (P493) by blocking DNA replication, leading to cell death and fragmentation. In mice harboring P493 tumor xenografts, BPTES treatment inhibited tumor cell growth; however, P493 xenografts expressing a BPTES-resistant GLS mutant (GLS-K325A) or overexpressing GLS were not affected by BPTES treatment. Moreover, a customized Vivo-Morpholino that targets human GLS mRNA markedly inhibited P493 xenograft growth without affecting mouse Gls expression. Conversely, a Vivo-Morpholino directed at mouse Gls had no antitumor activity in vivo. Collectively, our studies demonstrate that GLS is required for tumorigenesis and support small molecule and genetic inhibition of GLS as potential approaches for targeting the tumor cell–autonomous dependence on GLS for cancer therapy.

Authors

Yan Xiang, Zachary E. Stine, Jinsong Xia, Yunqi Lu, Roddy S. O’Connor, Brian J. Altman, Annie L. Hsieh, Arvin M. Gouw, Ajit G. Thomas, Ping Gao, Linchong Sun, Libing Song, Benedict Yan, Barbara S. Slusher, Jingli Zhuo, London L. Ooi, Caroline G.L. Lee, Anthony Mancuso, Andrew S. McCallion, Anne Le, Michael C. Milone, Stephen Rayport, Dean W. Felsher, Chi V. Dang

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Figure 6

On-target inhibition of GLS by BPTES in vivo.

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On-target inhibition of GLS by BPTES in vivo. (A) BPTES inhibited P493 x...
(A) BPTES inhibited P493 xenograft growth in vivo. n = 5. Day 10, P = 0.001. (B) Measurement of tumor glutamine and glutamate ratios shows on-target effect of BPTES in P493 parental cell line xenografts in vivo. n = 5. Day 10, P = 0.57. (C) BPTES failed to inhibit the growth of P493 xenografts overexpressing V5-GAC. n = 5. P = 0.50. (D) BPTES treatment elevated tumor glutamine levels and decreased glutamate levels in wild-type P493 xenografts in vivo. n = 5. (E) V5-GLS K325A overexpression rescues BPTES increase in glutamine and decrease in glutamate in P493 xenografts in vivo. n = 5. Values are shown as mean ± SD. Student’s t test was used.