STAT-3 Signaling Pathway Critical to Tumor Cell Survival

Signal transducers and activators of transcription (STATs) are transcription factors that are phosphorylated by JAK kinases in response to cytokine activation of a cell surface receptor tyrosine kinase. Upon activation, the STATs dimerize and are localized to the nucleus where they activate transcription of cytokine-responsive genes. There are at least three JAK kinases and at least six STAT proteins involved in this complex signaling pathway. Cytokines that activate STAT-3 include growth hormone, IL-6 family cytokines, and G-CSF. STAT-3, as well as STAT-5, induces progression through the cell cycle, prevents apoptosis, and upregulates oncogenes, such as c-myc and bcl-X and may play a role in oncogenesis.

Investigators at the University of South Florida College of Medicine (Tampa, USA) found that constitutive activation of STAT-3 suppressed tumor expression of proinflammatory mediators. Blocking STAT-3 in tumor cells increased expression of proinflammatory cytokines and chemokines that activated innate immunity and dendritic cells, leading to tumor-specific T-cell responses. These findings were published in the January 2004 issue of Nature Medicine.
The authors concluded that their findings allowed them to propose, "Tumor STAT-3 activity can mediate immune evasion by blocking both the production and sensing of inflammatory signals by multiple components of the immune system.”




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