期刊
EMBO JOURNAL
卷 28, 期 6, 页码 677-685出版社
WILEY
DOI: 10.1038/emboj.2009.8
关键词
autophagy; cancer; cell death; signalling; TRAIL
资金
- Danish Cancer Society
- Novo Nordisk Foundation
- Danish National Research Foundation
- Danish Medical Research Council
- European Commission [FP7]
- Meyer Foundation
- Ministerio de Educacion y Ciencia (MEC) [SAF2006-00633]
- Junta de Andalucia [CTS-211]
- Red Tematica de Investigacion Cooperativa en Cancer [RD06/0020/0068]
- Consejo Superior de Investigaciones Cientificas
The capacity of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) to trigger apoptosis preferentially in cancer cells, although sparing normal cells, has motivated clinical development of TRAIL receptor agonists as anti-cancer therapeutics. The molecular mechanisms responsible for the differential TRAIL sensitivity of normal and cancer cells are, however, poorly understood. Here, we show a novel signalling pathway that activates cytoprotective autophagy in untransformed human epithelial cells treated with TRAIL. TRAIL-induced autophagy is mediated by the AMP-activated protein kinase (AMPK) that inhibits mammalian target of rapamycin complex 1, a potent inhibitor of autophagy. Interestingly, the TRAIL-induced AMPK activation is refractory to the depletion of the two known AMPK-activating kinases, LKB1 and Ca(2+)/calmodulin-dependent kinase kinase-beta, but depends on transforming growth factor-beta-activating kinase 1 (TAK1) and TAK1-binding subunit 2. As TAK1 and AMPK are ubiquitously expressed kinases activated by numerous cytokines and developmental cues, these data are most likely to have broad implications for our understanding of cellular control of energy homoeostasis as well as the resistance of untransformed cells against TRAIL-induced apoptosis.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据