The transcription factor STAT3 is considered an oncogene being constitutively activated in as many as 70% primary human tumours, which often become addicted to its activity. However, the molecular bases for its essential role in tumours of different origin are incompletely understood. In order to generate a suitable model to address this question we have generated by knock-in mice expressing only the constitutively active form STAT3-C, in which STAT3 activity is similar to the continuous but relatively low activity observed in many tumours. STAT3C/C MEFs display increased proliferative potential, accelerated cell cycle, enhanced ability to grow past confluence and resistance to apoptotic stimuli and to spontaneous senescence. Surprisingly, a microarray analysis comparing STAT3C/C and STAT3wt/wt cells revealed profoundly modified expression of many genes involved in cell metabolism. STAT3C/C MEFs display reduced mitochondrial activity and accumulate less ROS, but activate aerobic glycolysis as shown by enhanced expression of master regulators of glycolysis such as PDK-1 and HIF-1, and by increased lactate production, glucose avidity and sensitivity to glycolysis inhibitors. The dependence of Stat3C/C MEFs on glycolysis is attenuated by the silencing of HIF-1. Moreover, STAT3C/C MEFs immortalized with a 3T3 protocol are transformed and able to form tumours in nude mice, and the transformation capacity is down-regulated by HIF-1 silencing. The idea that STAT3 could contribute to cell transformation and resistance to senescence by acting on cell metabolism is confirmed by our observation that inhibition of STAT3 activity in STAT3-addicted tumour cell lines partially restores mitochondrial activity and down-regulates glycolytic metabolism. Since most cancer cells are known to alter their glucose metabolism by activating anaerobic-like glycolysis despite available oxygen while down-regulating oxidative phosphorylation, a phenomenon known as ‘Warburg effect’, we propose that the essential role observed for STAT3 in so many different types of cancer may be explained by its ability to act as a molecular switch of cellular metabolism to trigger abnormal cell survival.
Metabolic switch between oxidative phosphorylation and glycolysis: a new role for Stat3 in tumours
DEMARIA, MARCO;MISALE, SANDRA;CAMPOREALE, ANNALISA;PROVERO, Paolo;POLI, Valeria
2010-01-01
Abstract
The transcription factor STAT3 is considered an oncogene being constitutively activated in as many as 70% primary human tumours, which often become addicted to its activity. However, the molecular bases for its essential role in tumours of different origin are incompletely understood. In order to generate a suitable model to address this question we have generated by knock-in mice expressing only the constitutively active form STAT3-C, in which STAT3 activity is similar to the continuous but relatively low activity observed in many tumours. STAT3C/C MEFs display increased proliferative potential, accelerated cell cycle, enhanced ability to grow past confluence and resistance to apoptotic stimuli and to spontaneous senescence. Surprisingly, a microarray analysis comparing STAT3C/C and STAT3wt/wt cells revealed profoundly modified expression of many genes involved in cell metabolism. STAT3C/C MEFs display reduced mitochondrial activity and accumulate less ROS, but activate aerobic glycolysis as shown by enhanced expression of master regulators of glycolysis such as PDK-1 and HIF-1, and by increased lactate production, glucose avidity and sensitivity to glycolysis inhibitors. The dependence of Stat3C/C MEFs on glycolysis is attenuated by the silencing of HIF-1. Moreover, STAT3C/C MEFs immortalized with a 3T3 protocol are transformed and able to form tumours in nude mice, and the transformation capacity is down-regulated by HIF-1 silencing. The idea that STAT3 could contribute to cell transformation and resistance to senescence by acting on cell metabolism is confirmed by our observation that inhibition of STAT3 activity in STAT3-addicted tumour cell lines partially restores mitochondrial activity and down-regulates glycolytic metabolism. Since most cancer cells are known to alter their glucose metabolism by activating anaerobic-like glycolysis despite available oxygen while down-regulating oxidative phosphorylation, a phenomenon known as ‘Warburg effect’, we propose that the essential role observed for STAT3 in so many different types of cancer may be explained by its ability to act as a molecular switch of cellular metabolism to trigger abnormal cell survival.
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