TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations.
TRB3 links insulin/IGF to tumour promotion by interacting with p62 and impeding autophagic/proteasomal degradations.
复制标题
TRB3 通过与 p62 相互作用并阻止自噬/蛋白酶体降解，将胰岛素/IGF 与肿瘤促进联系起来
DOI：
10.1038/ncomms8951
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发表时间：
2015-08-13
影响因子：
16.6
通讯作者：
Hu ZW
中科院分区：
文献类型：
--
作者：
Hua F;Li K;Yu JJ;Lv XX;Yan J;Zhang XW;Sun W;Lin H;Shang S;Wang F;Cui B;Mu R;Huang B;Jiang JD;Hu ZW
高胰岛素/IGF是糖尿病和癌症之间的生物学联系，但潜在的分子机制仍不清楚。在这里，我们报告了一个以前未被认识到的应激蛋白TRB 3的肿瘤促进机制，它介导自噬和蛋白酶体降解系统之间的相互拮抗作用，并将胰岛素/IGF与恶性促进联系起来。我们发现几种人类癌症表达较高的TRB 3和磷酸化胰岛素受体底物1，这与患者的预后呈负相关。TRB 3耗竭可防止胰岛素/IGF的促肿瘤作用，并减弱小鼠中的肿瘤起始、生长和转移。TRB 3与自噬受体p62相互作用并阻碍p62与LC 3和泛素化底物结合，这导致p62沉积并抑制自噬/蛋白酶体降解。几种肿瘤促进因子在癌细胞中积累以支持肿瘤代谢、增殖、侵袭和转移。中断TRB 3/p62相互作用产生针对肿瘤生长和转移的有效抗肿瘤功效。我们的研究开辟了靶向这种相互作用作为治疗糖尿病癌症的潜在新策略的可能性。
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.