蛋白激酶B
PI3K/AKT/mTOR通路
癌症研究
细胞生长
梅克尔细胞癌
下调和上调
葛兰素史克-3
生物
癌变
信号转导
细胞生物学
癌
生物化学
遗传学
基因
作者
JH Wu,Allison L Limmer,Deepika Narayanan,Hung Q. Doan,Rebecca A. Simonette,Peter L. Rady,Stephen K. Tyring
摘要
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine neoplasm of the skin, which has an exceedingly poor prognosis. The AKT/mammalian target of rapamycin (mTOR) signalling pathway, which plays a pivotal role in the modulation of protein synthesis and cell survival, has been shown to be extremely important for Merkel cell carcinogenesis. In the current study, we found that AKT has important regulatory functions in MCC cells and that inhibition of AKT with the novel ATP-competitive AKT inhibitor, afuresertib, has widespread effects on proliferative pathways. In particular, we found that treatment of MCC cells with afuresertib led to deactivation of mTOR and glycogen synthase kinase 3 pathway proteins while increasing activation of proapoptotic pathways through the upregulation of p16 expression and phosphomodulation of the B-cell lymphoma-2-associated death promoter. Overall, afuresertib treatment led to significant and robust inhibition of MCC cell proliferation, thus raising intriguing questions regarding the potential efficacy of AKT inhibition for the future clinical management of MCC.
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