Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells

Signal transducers and activators of transcription (STATs) are transcriptio n factors activated in response to cytokines and growth factors. Constituti vely active Stat3 has been shown to mediate oncogenic transformation in cul tured cells and induce tumor formation in mice. An increasing number of tum or-derived cell lines as well as samples from human cancer have been report ed to express constitutively active Stat3 protein. We previously demonstrat ed that ovarian cancer cell lines express high levels of constitutively act ive Stat3. In this study, we show that inhibition of the Stat3 signaling pa thway using the Janus Kinase-selective inhibitor, AG490, and a dominant neg ative Stat3 (Stat3 beta) significantly suppresses the growth of ovarian and breast cancer cell lines harboring constitutively active Stat3. In the ova rian cancer cell lines, AG490 also diminished the phosphorylation of Stat3, Stat3 DNA binding activity, and the expression of Bcl-X-L. Further, AG490 induced significant apoptosis in ovarian and breast cancer cell lines expre ssing high levels of constitutively active Stat3 but had a less profound ef fect on normal cells lacking constitutively active Stat3. AG490 also enhanc ed apoptosis induced by cisplatin in ovarian cancer cells. These results su ggest that inhibition of Stat3 signaling may provide a potential therapeuti c approach for treating ovarian and breast cancers.