STAT proteins: novel molecular targets for cancer drug discovery

Signal Transducers and Activators of Transcription (STATs) are a family of cytoplasmic proteins with roles as signal messengers and transcription fact ors that participate in normal cellular responses to cytokines and growth f actors. Frequently, however, abnormal activity of certain STAT family membe rs, particularly Stat3 and Stat5, is associated with a wide variety of huma n malignancies, including hematologic, breast, head and neck, and prostate cancers. Application of molecular biology and pharmacology tools in disease -relevant models has confirmed Stat3 as having a causal role in oncogenesis , and provided validation of Stat3 as a target for cancer drug discovery an d therapeutic intervention. Futhermore, a constitutively-active mutant form of Stat3 is sufficient to induce oncogenic transformation of cells, which form tumors in vivo. Constitutive activation of Stat3 signaling is accompan ied by upregulation of cyclin D1, c-Myc, and Bcl-x, changes consistent with subversion of normal cellular growth and survival control mechanisms. Bloc k of constitutive Stat3 signaling results in growth inhibition and apoptosi s of Stat3-positive tumor cells in vitro and in vivo. The observed dependen ce of certain tumors on constitutive Stat3 signaling for growth and surviva l has wide implications for cancer therapy, offering the potential for pref erential tumor cell killing. This review evaluates constitutive Stat3 activ ation as a 'cancer-causing' factor, and proposes a number of molecular stra tegies for targeting Stat3 signaling for therapeutic intervention.