Mitochondrial STAT3 Supports Ras-Dependent Oncogenic Transformation

• Published in: Science (American Association for the Advancement of Science) Vol. 324; no. 5935; pp. 1713 - 1716
• Main Authors: Gough, Daniel J, Corlett, Alicia, Schlessinger, Karni, Wegrzyn, Joanna, Larner, Andrew C, Levy, David E
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 26-06-2009; The American Association for the Advancement of Science
• Subjects: Animals; Cancer; Cell growth; Cell Line; Cell Line, Tumor; Cell lines; Cell Nucleus - metabolism; Cell Proliferation; Cell Survival; Cell Transformation, Neoplastic; Cells; Cellular biology; Cytokines; Epithelial cells; Genes, ras; Glycolysis; Mathematical transformations; Membrane Potential, Mitochondrial; Mice; Mice, Inbred BALB C; Mitochondria; Mitochondria - metabolism; Mitochondrial DNA; Mutant Proteins - metabolism; Neoplasms, Experimental - metabolism; Neoplasms, Experimental - pathology; Neoplastic Stem Cells; Oxidative Phosphorylation; Phosphorylation; Proteins; ras Proteins - metabolism; Signal Transduction; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Transformed cell line; Tumors
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1171721

Signal transducer and activator of transcription 3 (STAT3) is a latent cytoplasmic transcription factor responsive to cytokine signaling and tyrosine kinase oncoproteins by nuclear translocation when it is tyrosine-phosphorylated. We report 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. Moreover, STAT3 mutants that cannot be tyrosine-phosphorylated, that are retained in the cytoplasm, or that cannot bind DNA nonetheless supported Ras-mediated transformation. Unexpectedly, STAT3 was detected within mitochondria, and exclusive targeting of STAT3 to mitochondria without nuclear accumulation facilitated Ras transformation. Mitochondrial STAT3 sustained altered glycolytic and oxidative phosphorylation activities characteristic of cancer cells. Thus, in addition to its nuclear transcriptional role, STAT3 regulates a metabolic function in mitochondria, supporting Ras-dependent malignant transformation.