Targeting the p90RSK/MDM2/p53 Pathway Is Effective in Blocking Tumors with Oncogenic Up-Regulation of the MAPK Pathway Such as Melanoma and Lung Cancer

first_pagesettingsOrder Article Reprints Open AccessArticle Targeting the p90RSK/MDM2/p53 Pathway Is Effective in Blocking Tumors with Oncogenic Up-Regulation of the MAPK Pathway Such as Melanoma and Lung Cancer by Immacolata Maietta 1ORCID,Eleonora Viscusi 2,Stefano Laudati 3ORCID,Giuseppe Iannaci 2,Antonio D’Antonio 3,Rosa Marina Melillo 1,4ORCID,Maria Letizia Motti 5,*,†ORCID andValentina De Falco 1,*,†ORCID 1 Institute of Endocrinology and Experimental Oncology (IEOS), National Research Council (CNR), Via S. Pansini 5, 80131 Naples, Italy 2 U.O.C. Anatomia Patologica, P.O. Pellegrini ASL NA1 Centro, 80134 Naples, Italy 3 U.O.C. Anatomia Patologica, Ospedale del Mare ASL NA1 Centro, 80147 Naples, Italy 4 Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy 5 Department of Medical, Movement and Wellbeing Sciences, University of Naples Parthenope, 80133 Naples, Italy * Authors to whom correspondence should be addressed. † These authors contributed equally to this work. Cells 2024, 13(18), 1546; https://doi.org/10.3390/cells13181546 (registering DOI) Submission received: 9 August 2024 / Revised: 5 September 2024 / Accepted: 11 September 2024 / Published: 14 September 2024 (This article belongs to the Topic Kinases in Cancer and Other Diseases, 2nd Edition) Downloadkeyboard_arrow_down Browse Figures Versions Notes Abstract In most human tumors, the MAPK pathway is constitutively activated. Since p90RSK is downstream of MAPK, it is often hyperactive and capable of phosphorylating oncogenic substrates. We have previously shown that p90RSK phosphorylates MDM2 at S166, promoting p53 degradation in follicular thyroid carcinomas. Thus, the inhibition of p90RSK restores p53 expression, which in turn inhibits cell proliferation and promotes apoptosis. In the present study, we demonstrated that the p90RSK/MDM2/p53 pathway proved to be an excellent target in the therapy of tumors with MAPK hyperactivation. For this purpose, we selected p53wt melanoma, lung and medullary thyroid carcinoma cell lines with high activation of p90RSK. In these cell lines, we demonstrated that the p90RSK/MDM2/p53 pathway is implicated in the regulation of the cell cycle and apoptosis through p53-dependent transcriptional control of p21 and Bcl-2. Furthermore, with an immunohistochemical evaluation of primary melanomas and lung tumors, which exhibit highly activated p90RSK compared to corresponding normal tissue, we demonstrated that MDM2 stabilization was associated with p90RSK phosphorylation. The results indicate that p90RSK is able to control the proliferative rate and induction of apoptosis through the regulation of p53wt levels by stabilizing MDM2 in selected tumors with constitutively activated MAPKs, making p90RSK a new attractive target for anticancer therapy.