Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis.
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.
Yan
Y
Xiang
Zachary E
ZE
Stine
Jinsong
J
Xia
Yunqi
Y
Lu
Roddy S
RS
O'Connor
Brian J
BJ
Altman
Annie L
AL
Hsieh
Arvin M
AM
Gouw
Ajit G
AG
Thomas
Ping
P
Gao
Linchong
L
Sun
Libing
L
Song
Benedict
B
Yan
Barbara S
BS
Slusher
Jingli
J
Zhuo
London L
LL
Ooi
Caroline G L
CG
Lee
Anthony
A
Mancuso
Andrew S
AS
McCallion
Anne
A
Le
Michael C
MC
Milone
Stephen
S
Rayport
Dean W
DW
Felsher
Chi V
CV
Dang
D019943:Amino Acid Substitution; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005972:Glutaminase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D064593:Heterografts; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009368:Neoplasm Transplantation; D013440:Sulfides / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology
D013440:Sulfides; D013830:Thiadiazoles; C523193:bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl)ethyl sulfide; D005972:Glutaminase