Dopamine and cAMP‐regulated phosphoprotein 32kDa (DARPP‐32), protein phosphatase‐1 and cyclin‐dependent kinase 5 expression in ovarian cancer

Martin, Stewart G.; Zhang, Siwei; Yang, Song; Saidy, Behnaz; Deen, Suha; Storr, Sarah J.

Abstract

Dopamine and cyclic‐AMP activated phosphoprotein Mr32kDa (DARPP‐32) is a central signalling protein in neurotransmission. Following DARPP‐32 phosphorylation by protein kinase A (PKA), DARPP‐32 becomes a potent protein phosphatase 1 (PP1) inhibitor. DARPP‐32 can itself inhibit PKA following DARPP‐32 phosphorylation by cyclin‐dependent kinase 5 (Cdk5). Increasing evidence indicates a role for DARPP‐32 and its associated signalling pathways in cancer; however, its role in ovarian cancer remains unclear. Using immunohistochemistry, expression of DARPP‐32, PP1 and Cdk5 was determined in a large cohort of primary tumours from ovarian cancer patients (n = 428, 445 and 434 respectively) to evaluate associations between clinical outcome and clinicopathological criteria. Low cytoplasmic and nuclear DARPP‐32 expression was associated with shorter patient overall survival and progression‐free survival (P = .001, .001, .004 and .037 respectively). Low nuclear and cytoplasmic DARPP‐32 expression remained significantly associated with overall survival in multivariate Cox regression (P = .045, hazard ratio (HR) = 0.734, 95% confidence interval (CI) = 0.542‐0.993 and P = .001, HR = 0.494, 95% CI = 0.325‐0.749, respectively). High cytoplasmic and nuclear PP1 expression was associated with shorter patient overall survival and high cytoplasmic PP1 expression with shorter progression‐free survival (P = .005, .033, and .037, respectively). High Cdk5 expression was associated with shorter progression‐free survival (P = .006). These data suggest a role for DARPP‐32 and associated signalling kinases as prognostic markers with clinical utility in ovarian cancer.

Citation

Martin, S. G., Zhang, S., Yang, S., Saidy, B., Deen, S., & Storr, S. J. (2020). Dopamine and cAMP‐regulated phosphoprotein 32kDa (DARPP‐32), protein phosphatase‐1 and cyclin‐dependent kinase 5 expression in ovarian cancer. Journal of Cellular and Molecular Medicine, 24(16), 9165-9175. https://doi.org/10.1111/jcmm.15553

• Journal Article Type: Article
• Acceptance Date: Jun 7, 2020
• Online Publication Date: Jun 25, 2020
• Publication Date: 2020-08
• Deposit Date: Oct 12, 2020
• Publicly Available Date: Oct 12, 2020
• Journal: Journal of Cellular and Molecular Medicine
• Print ISSN: 1582-1838
• Electronic ISSN: 1582-4934
• Publisher: Wiley
• Peer Reviewed: Peer Reviewed
• Volume: 24
• Issue: 16
• Pages: 9165-9175
• DOI: https://doi.org/10.1111/jcmm.15553
• Keywords: Molecular Medicine; Cell Biology
• Public URL: https://nottingham-repository.worktribe.com/output/4736754
• Publisher URL: https://onlinelibrary.wiley.com/doi/full/10.1111/jcmm.15553