Loss of BCAA Catabolism during Carcinogenesis Enhances mTORC1 Activity and Promotes Tumor Development and Progression

被引：219

作者：

Ericksen, Russell E. ^{[1
]}

Lim, Siew Lan ^{[1
]}

McDonnell, Eoin ^{[2
]}

Shuen, Wai Ho ^{[3
]}

Vadiveloo, Maya ^{[4
]}

White, Phillip J. ^{[2
]}

Ding, Zhaobing ^{[1
]}

Kwok, Royston ^{[1
]}

Lee, Philip ^{[1
]}

Radda, George K. ^{[1
]}

Toh, Han Chong ^{[3
]}

Hirschey, Matthew D. ^{[2
]}

Han, Weiping ^{[1
]}

机构：

[1] Agcy Sci Technol & Res, Singapore Bioimaging Consortium, 11 Biopolis Way, Singapore 138667, Singapore

[2] Duke Mol Physiol Inst, 300 North Duke St, Durham, NC 27701 USA

[3] Natl Canc Ctr Singapore, Div Med Oncol, 11 Hosp Dr, Singapore 169610, Singapore

[4] Univ Rhode Isl, Dept Nutr & Food Sci, 41 Lower Coll Rd, Kingston, RI 02881 USA

来源：

CELL METABOLISM | 2019年 / 29卷 / 05期

关键词：

COMPREHENSIVE MOLECULAR CHARACTERIZATION; CHAIN AMINO-ACIDS; HEPATOCELLULAR-CARCINOMA; GENOMIC CHARACTERIZATION; CANCER; LIVER; DIETARY; PATHWAY; TUMORIGENESIS; RISK;

D O I：

10.1016/j.cmet.2018.12.020

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Tumors display profound changes in cellular metabolism, yet how these changes aid the development and growth of tumors is not fully understood. Here we use a multi-omic approach to examine liver carcinogenesis and regeneration, and find that progressive loss of branched-chain amino acid (BCAA) catabolism promotes tumor development and growth. In human hepatocellular carcinomas and animal models of liver cancer, suppression of BCAA catabolic enzyme expression led to BCAA accumulation in tumors, though this was not observed in regenerating liver tissues. The degree of enzyme suppression strongly correlated with tumor aggressiveness, and was an independent predictor of clinical outcome. Moreover, modulating BCAA accumulation regulated cancer cell proliferation in vitro, and tumor burden and overall survival in vivo. Dietary BCAA intake in humans also correlated with cancer mortality risk. In summary, loss of BCAA catabolism in tumors confers functional advantages, which could be exploited by therapeutic interventions in certain cancers.

引用

页码：1151 / +

页数：21

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