Ras, STAT3, and Transformation: The STAT (signal transducer and activator of transcription) proteins are activated in response to receptor stimulation and act in the nucleus to regulate gene expression. Gough et al. (p. 1713 ) found that STAT3 functioned in transformation of cells by the oncogene Ras. However, this activity was maintained in mutants of STAT that fail to activate transcription. Instead, the active STAT3 appeared to be associated with mitochondria. Furthermore, modified STAT3 targeted to the mitochondria promoted transformation by Ras, and mitochondrial function was disrupted in Ras-transformed cells lacking STAT3. Such transformation-specific effects of STAT3 could be a useful target in developing anticancer therapies.

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.