TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations

被引：139

作者：

Hua, Fang ^{[1
]}

Li, Ke ^{[1
,2
]}

Yu, Jiao-Jiao ^{[1
]}

Lv, Xiao-Xi ^{[1
]}

Yan, Jun ^{[1
]}

Zhang, Xiao-Wei ^{[1
]}

Sun, Wei ^{[1
]}

Lin, Heng ^{[1
]}

Shang, Shuang ^{[1
]}

Wang, Feng ^{[1
]}

Cui, Bing ^{[1
]}

Mu, Rong ^{[1
]}

Huang, Bo ^{[3
]}

Jiang, Jian-Dong ^{[1
,2
]}

Hu, Zhuo-Wei ^{[1
]}

机构：

[1] Chinese Acad Med Sci, Peking Union Med Coll, Inst Mat Med, Immunol & Canc Pharmacol Grp,State Key Lab Bioact, Beijing 100050, Peoples R China

[2] Chinese Acad Med Sci, Peking Union Med Coll, Inst Med Biotechnol, Beijing 100005, Peoples R China

[3] Chinese Acad Med Sci, Peking Union Med Coll, Inst Basic Med Sci, Beijing 100005, Peoples R China

来源：

NATURE COMMUNICATIONS | 2015年 / 6卷

基金：

中国国家自然科学基金;

关键词：

PROTEIN-PROTEIN INTERACTIONS; CANCER-RISK; TRIBBLES HOMOLOG; AUTOPHAGY; CELLS; METASTASIS; ACTIVATION; OBESITY; BETA; P62/SQSTM1;

D O I：

10.1038/ncomms8951

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

High insulin/IGF is a biologic link between diabetes and cancers, but the underlying molecular mechanism remains unclear. Here we report a previously unrecognized tumour-promoting mechanism for stress protein TRB3, which mediates a reciprocal antagonism between autophagic and proteasomal degradation systems and connects insulin/IGF to malignant promotion. We find that several human cancers express higher TRB3 and phosphorylated insulin receptor substrate 1, which correlates negatively with patient's prognosis. TRB3 depletion protects against tumour-promoting actions of insulin/IGF and attenuates tumour initiation, growth and metastasis in mice. TRB3 interacts with autophagic receptor p62 and hinders p62 binding to LC3 and ubiquitinated substrates, which causes p62 deposition and suppresses autophagic/proteasomal degradation. Several tumour-promoting factors accumulate in cancer cells to support tumour metabolism, proliferation, invasion and metastasis. Interrupting TRB3/p62 interaction produces potent antitumour efficacies against tumour growth and metastasis. Our study opens possibility of targeting this interaction as a potential novel strategy against cancers with diabetes.

引用

页数：16

共 53 条

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