Post-translational modifications of STAT3: Modulators of androgen-resistance in prostate cancer

Abstract

“Androgen Escape” is a clinical phase in which cancer-associated prostatic cells become able to survive and proliferate without circulated androgens. This reflects a more aggressive tumor development form with worse prognosis. Then, cell survival and proliferation can be under control of non-canonical mechanisms and some of these pathways involved the protein STAT3 (Signal Transducer and Activator of Transcription). STAT3 activation can regulate genes expression and subsequently cell proliferation, differentiation and apoptosis. In prostate cancer, androgenic and STAT3 pathways are constitutively activated, cross-talking differently in a hormone-responsive or hormone-refractory tumor [1,2]. Considering this, the aim of our study was to assess the involvement of STAT3 and its post-translational modifications (PTMs) in the androgen escape process in two different human prostate cancer cell lines, LNCaP (androgen-responsive) and PC3 (androgen-refractory). Both cell lines were stimulated by IL-6, EGF and H2O2 to mimic inflammatory and oxidative conditions. The acetylated STAT3 form, expressed in low Gleason Score and in inflammatory process [3], increased after IL-6 treatment in both cell lines. Under the same treatment conditions, in LNCaP there was an overexpression of genes, which inhibit cell proliferation, illustrating LNCaP lower aggressiveness. On the other hand, the glutathionylated STAT3, typical of high Gleason Score and of oxidative conditions [3], was constitutively expressed in PC3 untreated cells and in LNCaP only after H2O2 treatment, indicating a higher aggressiveness of PC3 cells. Therefore, we can speculate a functional role of STAT3 and its PTMs in the “Androgen Escape” trigger.