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[Cancer Research 59, 5059-5063, October 1, 1999]
© 1999 American Association for Cancer Research
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[Cancer Research 59, 5059-5063, October 15, 1999]
© 1999 American Association for Cancer Research

Advances in Brief

Gene Therapy with Dominant-negative Stat3 Suppresses Growth of the Murine Melanoma B16 Tumor in Vivo1

Guilian Niu2, Richard Heller2, Robyn Catlett-Falcone, Domenico Coppola, Mark Jaroszeski, William Dalton, Richard Jove and Hua Yu3

Immunology Program [G. N., H. Y.], Clinical Investigations Program [R. H., D. C., W. D.], and Molecular Oncology Program [R. C-F., R. J.], H. Lee Moffitt Cancer Center and Research Institute, and Departments of Microbiology and Immunology [G. N., R. H., H. Y.], Surgery [R. H., M. J.], Pathology [R. C-F., D. C.], Medicine [W. D.], and Biochemistry and Molecular Biology [R. J.], University of South Florida College of Medicine, Tampa, Florida 33612

Whereas signal transducers and activators of transcription were originally discovered as mediators of normal cytokine signaling, constitutive activation of certain signal transducer and activator of transcription proteins, including Stat3, has been found in increasing numbers of human cancers. Recently, a causal role for Stat3 activation in oncogenesis has been demonstrated, suggesting that Stat3 represents a novel target for cancer therapy. We report here that in vitro expression of a Stat3 variant with dominant-negative 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, suggesting 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 inhibition of tumor growth as well as tumor regression. This Stat3{beta}-induced antitumor effect is associated with apoptosis of the B16 tumor cells in vivo. These findings demonstrate for the first time that interfering with Stat3 signaling induces potent antitumor activity in vivo and thus identify Stat3 as a potential molecular target for therapy of human cancers harboring activated Stat3.




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