Transcription Factor May Be Prostate Cancer Drug Target

Cancer researchers have identified a signaling protein in prostate cancer cells that they suggest would be an attractive target for directed chemotherapy.

The protein in question is a member of the STAT (signal transducer and transcription) family of transcription factors and is referred to as Stat5. In response to cytokines and growth factors, STAT family members are phosphorylated by their receptor-associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. Stat5 is activated by, and mediates, the responses of many cell ligands, such as IL2, IL3, IL7 GM-CSF, erythropoietin, thrombopoietin, and different growth hormones

Transcription factors are protein complexes that modulate RNA polymerase binding to DNA. RNA polymerase is the enzyme that transcribes genes in the nucleus to make messenger RNA, which is then used to make protein in the protoplasm. By controlling the access of RNA polymerase to the gene, transcription factors order the rate at which a gene is transcribed. Without transcription factors, cells would not be able to effectively regulate the rate at which genes are expressed.

Investigators at Thomas Jefferson University (Philadelphia, PA, USA) had previously found that patients with primary prostate cancer were more likely to have recurrent disease when Stat5 was expressed. In the current study, they evaluated prostate cancer cells from 198 patients with prostate cancer recurrence. They reported in the January 1, 2008 issue of the journal Cancer Research that Stat5 was active in 74% of all recurrent prostate cancers. Of these patients, 127 had been treated with androgen deprivation therapy. Stat5 was active in 95% of these hormone-resistant tumors, suggesting that hormone deprivation therapy was an activating factor for Stat5.

Another key finding of this study was that Stat5 synergized with androgen receptor (AR) in prostate cancer cells. Specifically, active Stat5 increased the transcriptional activity of AR, and AR, in turn, increased the transcriptional activity of Stat5. Bound AR and active Stat5 physically interacted in prostate cancer cells and enhanced nuclear localization of each other.

"These findings validate Stat5 as a potential drug target in prostate cancer, and in particular, in a form of prostate cancer for which there are no effective therapies,” said senior author Dr. Marja Nevalainen, associate professor of cancer biology at Thomas Jefferson University.


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