接合作用
IRS1
IRS2
胰岛素受体
胰岛素
PI3K/AKT/mTOR通路
癌症研究
胰岛素受体底物
高胰岛素血症
背景(考古学)
癌症
内分泌学
内科学
生物
信号转导
医学
胰岛素抵抗
细胞生物学
泛素连接酶
泛素
遗传学
基因
古生物学
作者
Jun Bum Park,Geon Ho Moon,Ara Cho,Minji Kwon,Jong-Wan Park,Eugene C. Yi,Haeryoung Kim,Junji Fukuda,Cheol Kwak,Young‐Gyu Ko,Yang Sook Chun
标识
DOI:10.1038/s41417-024-00729-z
摘要
Abstract Irregularities in insulin signaling have significantly increased the risk of various cancers, yet the precise underlying mechanisms remain unclear. Within our study, we observed that inhibiting neddylation enhances cancer cell migration across different cancer types by activating both insulin receptor substrates 1 and 2 (IRS1 and IRS2), along with the PI3K/AKT signaling pathway. Notably, in the context of high-grade serous carcinoma (HGSC) patients, whether they had type 2 diabetes mellitus or not, IRS1 and IRS2 displayed a parallel relationship with each other while exhibiting an inverse relationship with NEDD8. We also identified C-CBL as an E3 ligase responsible for neddylating IRS1 and IRS2, with clinical evidence further confirming a reciprocal relationship between C-CBL and pAKT, thereby reinforcing the tumor suppressive role of C-CBL. Altogether, these findings suggest that neddylation genuinely participates in IRS1 and IRS2-dependent insulin signaling, effectively suppressing cancer cell migration. Thus, caution is advised when considering neddylation inhibitors as a treatment option for cancer patients, particularly those presenting with insulin signaling dysregulations linked to conditions like obesity-related type 2 diabetes or hyperinsulinemia.
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