Gene therapy with dominant-negative Stat3 suppresses growth of the murine melanoma B16 tumor in vivo

Whereas signal transducers and activators of transcription were originally discovered as mediators of normal cytokine signaling, constitutive activati on of certain signal transducer and activator of transcription proteins, in cluding Stat3, has been found in increasing numbers of human cancers, Recen tly, a causal role for Stat3 activation in oncogenesis has been demonstrate d, suggesting that Stat3 represents a novel target for cancer therapy. We r eport here that in vitro expression of a Stat3 variant with dominant-negati ve properties, Stat3 beta, induced cell death in murine B16 melanoma cells that harbored activated Stat3. By contrast, expression of Stat3 beta had no effect on normal fibroblasts or the Stat3-negative murine tumor MethA, sug gesting that only tumor cells with activated Stat3 have become dependent on this pathway for survival. Significantly, gene therapy by electroinjection of the Stat3 beta expression vector into preexisting B16 tumors caused inh ibition of tumor growth as well as tumor regression. This Stat3 beta-induce d antitumor effect is associated with apoptosis of the B16 tumor cells in v ivo, These findings demonstrate for the first time that interfering with St at3 signaling induces potent antitumor activity in vivo and thus identify S tat3 as a potential molecular target for therapy of human cancers harboring activated Stat3.