The oncogenic protein kinase/ATPase RIOK1 is up-regulated via the MYC/E2F transcription factor axis in prostate cancer

The atypical protein kinase/ATPase RIOK1 is involved in pre-40S ribosomal subunit production, cell cycle progression and PRMT5 methylosome substrate recruitment. RIOK1 overexpression characterizes several malignancies and correlates with Cancer stage, therapy resistance, poor patient survival and other prognostic factors, but its role in prostate Cancer (PCa) is unknown. In this study, we examined the expression, regulation and therapeutic potential of RIOK1 in PCa. RIOK1 mRNA and protein expression were elevated in PCa tissue samples and correlated with proliferative and protein homeostasis related pathways. RIOK1 was identified as a downstream target gene of the MYC/E2F transcription factors. RIOK1 knock-down and over-expression of the dominant-negative RIOK1-D324A mutant significantly reduced proliferation of PCa cells. Biochemical inhibition of RIOK1 with toyocamycin led to strong anti-proliferative effects in AR-negative and -positive PCa cell lines with EC50 values from 3.5 to 8.8 nM. Toyocamycin resulted in a rapid decrease in RIOK1 protein expression, total rRNA content and a shift in the 28S/18S rRNA ratio. In addition, toyocamycin treatment strongly induced Apoptosis at a similar level as the clinically used chemotherapeutic drug docetaxel. In summary, RIOK1 is a part of the MYC oncogene network and as such, could be considered for future treatment of PCa.

atypical kinase; kinase inhibitors; prostate cancer; transcription factors.