A STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction.
A STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction.
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DOI：
10.18632/aging.100232
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发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Poli V
中科院分区：
文献类型：
--
作者：
Demaria M;Giorgi C;Lebiedzinska M;Esposito G;D'Angeli L;Bartoli A;Gough DJ;Turkson J;Levy DE;Watson CJ;Wieckowski MR;Provero P;Pinton P;Poli V
原癌转录因子STAT 3在各种肿瘤中被组成性激活，这些肿瘤通常对其活性上瘾，但尚未出现决定这种广泛的STAT 3依赖性的核心功能的统一观点。我们在这里表明，组成型活性STAT 3作为一个主调节细胞代谢，诱导有氧糖酵解和下调原代成纤维细胞和STAT 3依赖性肿瘤细胞系中的线粒体活性。因此，细胞被保护免于凋亡和衰老，同时变得对葡萄糖剥夺高度敏感。我们发现，糖酵解的增强依赖于HIF-1α的上调，而线粒体活性的降低则不依赖于HIF-1α，可能是由STAT 3介导的线粒体蛋白的下调引起的。有氧糖酵解的诱导是STAT 3促癌活性的重要组成部分，因为在体外和体内，抑制肿瘤细胞系中的STAT 3酪氨酸磷酸化在导致生长停滞和细胞死亡之前下调糖酵解。我们认为，这种新的中心代谢作用是许多生物学上不同的肿瘤所显示的STAT 3成瘾的核心。
The pro-oncogenic transcription factor STAT3 is constitutively activated in a wide variety of tumours that often become addicted to its activity, but no unifying view of a core function determining this widespread STAT3-dependence has yet emerged. We show here that constitutively active STAT3 acts as a master regulator of cell metabolism, inducing aerobic glycolysis and down-regulating mitochondrial activity both in primary fibroblasts and in STAT3-dependent tumour cell lines. As a result, cells are protected from apoptosis and senescence while becoming highly sensitive to glucose deprivation. We show that enhanced glycolysis is dependent on HIF-1α up-regulation, while reduced mitochondrial activity is HIF-1α-independent and likely caused by STAT3-mediated down-regulation of mitochondrial proteins. The induction of aerobic glycolysis is an important component of STAT3 pro-oncogenic activities, since inhibition of STAT3 tyrosine phosphorylation in the tumour cell lines down-regulates glycolysis prior to leading to growth arrest and cell death, both in vitro and in vivo. We propose that this novel, central metabolic role is at the core of the addiction for STAT3 shown by so many biologically different tumours.
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DOI：
10.1016/j.biocel.2009.04.010
发表时间：
2009-10
影响因子：
4
作者：
Giorgi, Carlotta;De Stefani, Diego;Bononi, Angela;Rizzuto, Rosario;Pinton, Paolo
通讯作者：
Pinton, Paolo
影响因子：
5.3
作者：
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通讯作者：
Darnell, JE
影响因子：
82.9
作者：
Chiarle, R;Simmons, WJ;Inghirami, G
通讯作者：
Inghirami, G
影响因子：
4.8
作者：
McFate, Thomas;Mohyeldin, Ahmed;Verma, Ajay
通讯作者：
Verma, Ajay
影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ