A STAT3-mediated metabolic switch is involved in tumour transformation and STAT3 addiction

Abstract

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.

From tissue invasion to glucose metabolism: the many aspects of signal transducer and activator of transcription 3 pro-oncogenic activities

“…STAT3 addiction in these cells is indeed linked to STAT3-induced glycolysis, as suggested by the observation that its inhibition down-regulates the glycolysis rate while up-regulating mitochondrial activity prior to leading to apoptotic cell death. Importantly, our data with tumour xenografts support the idea that STAT3 addiction occurs via the same mechanism also in vivo (11).…”

“…MEFs were prepared from 13.5 days embryos. Both MEFs and MDA-MB468 (ATCC, Manassas VA, USA) were grown as described (11). S3I-201 inhibitor was used at a concentration of 100 µM (MEFs and MDA-MB468) or 200 µM (C1 cells).…”

“…We sought then to assess whether primary Stat3 C/C MEFs displayed pre-oncogenic or transformed features (11). Stat3 C/C cells grew faster than their wild type controls and displayed an accelerated cell cycle, with a more rapid transit through S-phase (not shown).…”

“…Moreover, we discuss data showing that STAT3 acts as a master regulator of glucose metabolism and cellular respiration, and that its inhibition leads to apoptotic death of STAT3-dependent cancer cells at least partly via modifying their metabolic requirements (11).…”

A positive feedback loop between miR‐181b and STAT3 that affects Warburg effect in colon cancer via regulating PIAS3 expression

“…Recently, some studies reveal that STAT3 acts as a master regulator of aerobic glycolysis 14, 15, 16. STAT3 regulates the Warburg effect via promoting aerobic glycolysis and downregulating mitochondrial activity 16. Protein inhibitor of activated STAT 3 (PIAS3) is a specific inhibitor of STAT3.…”