STAT3 is a latent cytoplasmic transcription factor that responds to cytokine signaling and tyrosine kinase oncoproteins by nuclear translocation when tyrosine phosphorylated and has been implicated in a wide variety of human cancers. We have found that malignant transformation by activated Ras is impaired without STAT3, in spite of the inability of Ras to drive STAT3 tyrosine phosphorylation or nuclear translocation. STAT3 mutants that cannot be tyrosine phosphorylated, are retained in the cytoplasm, or cannot bind DNA are nonetheless capable of supporting Ras-mediated transformation. In addition to being a cytoplasmic protein that translocates to the nucleus in response to tyrosine phosphorylation, STAT3 accumulates in mitochondria, and its presence in mitochondria is sufficient to support Ras-mediated transformation. Mitochondrial STAT3 modulates metabolic output, influencing both glycolytic and oxidative phosphorylation activities characteristic of cancer cells. These actions of mitochondrial STAT3 depend on its phosphorylation on serine 727, which is mediated by the MEK-ERK pathway in Ras-transformed cells.

K-Ras-dependent myeloid proliferative neoplasm in mice displays serine but not tyrosine phosphorylated STAT3. A point mutation abrogating STAT3 S727 phosphorylation delayed onset and decreased disease severity in mice with oncogenic K-Ras expressed in  hematopoietic progenitors and significantly extended their survival. Activated K-Ras also required STAT3 for cytokine-independent growth of myeloid progenitors in vitro, and mitochondrially restricted STAT3 and STAT3-Y705F, both transcriptionally inert mutants, supported factor-independent cell growth. Although STAT3 was dispensable for growth of myeloid progenitors in response to cytokines, abrogation of STAT3-S727 phosphorylation blocked K-Ras-driven, growth factor-independent malignant growth. These data document that serine phosphorylated, mitochondrially-restricted STAT3 supports hematopoietic neoplastic cell growth induced by K-Ras. A series of small molecules that impair growth of malignant cells appear to depend on the metabolic function of STAT3, suggesting that mitochondrial STAT3 is a viable cancer target.