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Mitochondrial STAT3 supports Ras-dependent oncogenic transformation

Daniel J Gough1, Alicia Corlett, Karni Schlessinger

  • 1Department of Pathology and New York University Cancer Institute, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.

Science (New York, N.Y.)
|June 27, 2009
PubMed

Insights

Signal transducer and activator of transcription 3 (STAT3) supports Ras-driven cancer. STAT3

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Biology

Background:

  • Signal transducer and activator of transcription 3 (STAT3) is a transcription factor activated by phosphorylation.
  • STAT3 typically translocates to the nucleus to regulate gene expression.
  • Ras oncoproteins are known drivers of malignant transformation.

Purpose of the Study:

  • To investigate the role of STAT3 in Ras-mediated malignant transformation.
  • To determine if STAT3's canonical nuclear function is required for Ras transformation.
  • To explore non-canonical functions of STAT3 in cancer.

Main Methods:

  • Utilized Ras-transformed cell models.
  • Employed STAT3 mutants with impaired phosphorylation, nuclear translocation, or DNA binding.
  • Investigated STAT3 localization using cell biology techniques.
  • Assessed metabolic changes including glycolysis and oxidative phosphorylation.

Main Results:

  • Ras-mediated transformation was impaired in the absence of STAT3.
  • STAT3 mutants lacking canonical functions still supported Ras transformation.
  • STAT3 was found in mitochondria, independent of nuclear translocation.
  • Targeting STAT3 exclusively to mitochondria facilitated Ras transformation.
  • Mitochondrial STAT3 modulated cancer-associated metabolic pathways.

Conclusions:

  • STAT3 plays a crucial role in Ras-mediated malignant transformation beyond its nuclear transcriptional activity.
  • STAT3 possesses a non-canonical function within mitochondria that supports cancer metabolism.
  • Mitochondrial STAT3 directly contributes to the metabolic reprogramming essential for cancer cell survival and proliferation.

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