» Articles » PMID: 39329730

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

Overview
Journal Cells
Publisher MDPI
Date 2024 Sep 27
PMID 39329730
Authors
Affiliations
Soon will be listed here.
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 and . 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.

References
1.
Malumbres M, Barbacid M . RAS oncogenes: the first 30 years. Nat Rev Cancer. 2003; 3(6):459-65. DOI: 10.1038/nrc1097. View

2.
Moschos S, Sullivan R, Hwu W, Ramanathan R, Adjei A, Fong P . Development of MK-8353, an orally administered ERK1/2 inhibitor, in patients with advanced solid tumors. JCI Insight. 2018; 3(4). PMC: 5916243. DOI: 10.1172/jci.insight.92352. View

3.
Yoon S, Seger R . The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors. 2006; 24(1):21-44. DOI: 10.1080/02699050500284218. View

4.
Salvatore G, De Falco V, Salerno P, Nappi T, Pepe S, Troncone G . BRAF is a therapeutic target in aggressive thyroid carcinoma. Clin Cancer Res. 2006; 12(5):1623-9. DOI: 10.1158/1078-0432.CCR-05-2378. View

5.
Rusciano M, Salzano M, Monaco S, Sapio M, Illario M, De Falco V . The Ca2+-calmodulin-dependent kinase II is activated in papillary thyroid carcinoma (PTC) and mediates cell proliferation stimulated by RET/PTC. Endocr Relat Cancer. 2009; 17(1):113-23. DOI: 10.1677/ERC-09-0214. View