The p90 Ribosomal S6 Kinases 2 and 4 promote Prostate Cancer cell proliferation in androgen-dependent and independent ways

Abstract

Oncogenic activation of the phosphatidylinositol-3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways are frequent events in Prostate Cancer (PCa) that have been correlated to tumour formation, disease progression and therapeutic resistance. At the intersection of these two pathways lies the p90 ribosomal S6 kinase (RSKs) family, which regulates many proteins involved in cell survival, growth and proliferation. As such, deregulated RSKs activity has been associated with multiple cancer types, including PCa. However, the full extent of the RSKs involvement in prostate tumorigenesis remains to be determined. Here we have shown that RSKs levels are increased in PCa samples and cell lines. The RSKs were found to enhance Androgen Receptor (AR) activity, the key oncogenic driver in PCa. Indeed, all RSKs were found to interact in close proximity to the AR. However, RSK2/4, but not RSK1/3, showed changes in cell localisation following AR nuclear translocation. Consistently, silencing of RSK2/4, but not RSK1/3, inhibited PCa proliferation in an androgen-dependent and independent manner, respectively, and induced different signaling events downstream of the AR. The data suggests that RSK2 and RSK4 activity is required for PCa cell proliferation, but they are likely regulating growth via different mechanisms.