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Overexpression of a Dominant-Negative Signal Transducer and Activator of Transcription 3 Variant in Tumor Cells Leads to Production of SolubleFactors That Induce Apoptosis and Cell Cycle Arrest¹

Immunology Program [G. N., H. Y.], Clinical Investigations Program [K. S., W. D.], and Molecular Oncology Program [M. H., R. J.], H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33613; Department of Oncology, University of South Florida College of Medicine, Tampa, Florida 33612; and Johns Hopkins Oncology Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287 [R. R., A. B.]

Gene therapy of B16 tumors with a dominant-negative signal transducer and activator of transcription (Stat3) variant, designated Stat3ß, results in inhibition of tumor growth and tumor regression. Although only 10–15% of the tumor cells are transfected in vivo, the Stat3ß-induced antitumor effect is associated with massive apoptosis of B16 tumor cells, indicative of a potent bystander effect. Here, we provide evidence that blocking Stat3 signaling in B16 cells results in release of soluble factors that are capable of inducing apoptosis and cell cycle arrest of nontransfected B16 cells. RNase protection assays using multi-template probes specific for key physiological regulators of apoptosis reveal that overexpression of Stat3ß in B16 tumor cells induces the expression of the apoptotic effector, tumor necrosis factor-related apoptosis-inducing ligand. These in vitro results suggest that the observed in vivo bystander effect leading to tumor cell growth inhibition is mediated, at least in part, by soluble factors produced as a result of overexpression of Stat3ß in tumor cells.

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