The Oncogenic Protein Kinase/ATPase RIOK1 Is Up-Regulated via the c-myc/E2F Transcription Factor Axis in Prostate Cancer.

The atypical protein kinase/ATPase RIO kinase (RIOK)-1 is involved in pre-40S ribosomal subunit production, cell-cycle progression, and protein arginine N-methyltransferase 5 methylosome substrate recruitment. RIOK1 overexpression is a characteristic of several malignancies and is correlated with cancer stage, therapy resistance, poor patient survival, and other prognostic factors. However, its role in prostate cancer (PCa) is unknown. In this study, the expression, regulation, and therapeutic potential of RIOK1 in PCa were examined. 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 c-myc/E2F transcription factors. Proliferation of PCa cells was significantly reduced with RIOK1 knockdown and overexpression of the dominant-negative RIOK1-D324A mutant. Biochemical inhibition of RIOK1 with toyocamycin led to strong antiproliferative effects in androgen receptor-negative and -positive PCa cell lines with EC50 values of 3.5 to 8.8 nmol/L. Rapid decreases in RIOK1 protein expression and total rRNA content, and a shift in the 28S/18S rRNA ratio, were found with toyocamycin treatment. Apoptosis was induced with toyocamycin treatment at a level similar to that with the chemotherapeutic drug docetaxel used in clinical practice. In summary, the current study indicates that RIOK1 is a part of the MYC oncogene network, and as such, could be considered for future treatment of patients with PCa.

Recent Hints on the Dual Role of Discs Large MAGUK Scaffold Protein 5 in Cancers and in Hepatocellular Carcinoma.

Discs large MAGUK scaffold protein 5 (DLG5) is a multi-domain member of membrane-associated guanylate kinase (MAGUK) family, which plays a major role in the maintenance of cell epithelial polarity being part of the SCRIB-LGL-DLG complex. Although polarity proteins have been generally considered tumor suppressors, recent discoveries led to reconsidering their role in cancer. This is also true for DLG5 in different cancer types, including hepatocellular carcinoma (HCC). In this cancer, DLG5 was negatively associated with malignant characteristics, however recent findings associated DLG5 expression with advanced stages of HCC. In vitro studies evidenced its possible role in sustaining cell growth and migration by the interaction with several intracellular pathways, such as Hippo, Hedgehog, and PI3K/AKT signaling pathways. In this review, we summarize the recent finding on the dual role of DLG5 and other polarity proteins in cancers. What emerges is a still undefined role of those proteins in cancers, especially in HCC, one of the most frequent cancers worldwide, where the function of DLG5 and other polarity proteins is still largely unexplored.