| Summary: | The transcription factor STAT3 normally modulates cell proliferation with a rapid and transient downstream effect. However, in tumor cells, inappropriately activated STAT3 alters the gene expression profile and renders tumor cells unresponsive to cell death signals. In this study, we examine the biological and biochemical effects of some STAT3 inhibitors on ovarian and cervical cancer cells. Furthermore, we study the reciprocal relationship between STAT3 and NF-kB—another prosurvival transcription factor—in ovarian cancer cells.
Inappropriate activation of STAT3 occurs in many cancers and often results in resistance to conventional chemotherapies. In addition, overactive STAT3 signaling in tumor cells has been correlated with resistance to conventional chemotherapies. Therefore, for cancer patients, targeted inhibition of STAT3 potentially constitutes a powerful therapeutic tool. Initially, when ovarian cancer cells that depend on STAT3 for pathogenesis are treated with STAT3 inhibitors (i.e. nifuroxazide, ST3-01, etc), significantly reduced viability was observed. Surprisingly, results from quantitative RT-PCR analysis and reporter assays have identified an unexpected reciprocal relationship between STAT3 inhibition and NF-кB activation. Furthermore, reducing STAT3 expression by RNAi seemed to result in the upregulation of NF-кB genes including A20 and IL-8, which was consistent with the effects of STAT3 inhibitors. Moreover, the combination of reducing the levels of both STAT3 and the NF-кB subunit p65 was found to abrogate the upregulation of NF-кB target genes seen when STAT3 levels alone were reduced. This suggests that p65 expression is important for the activation of NF-кB by STAT3 inhibition. Subsequently, NF-кB nuclear translocation was examined in whole cell populations as well as in single cells. The results showed that no apparent p65 nuclear translocation was observed upon STAT3 inhibition, suggesting an alternative mechanism of NF-кB activation.
|
|---|
