RSK2 promotes melanoma cell proliferation and vemurafenib resistance via upregulating cyclin D1

Hai-Zhou Wu; Lan-Ya Li; Shi-Long Jiang; Yi-Zhi Li; Xiao-Mei Shi; Xin-Yuan Sun; Zhuo Li; Yan Cheng

doi:10.3389/fphar.2022.950571

RSK2 promotes melanoma cell proliferation and vemurafenib resistance via upregulating cyclin D1

Front Pharmacol. 2022 Sep 20:13:950571. doi: 10.3389/fphar.2022.950571. eCollection 2022.

Authors

Hai-Zhou Wu^{1

2}, Lan-Ya Li^{1

2}, Shi-Long Jiang¹, Yi-Zhi Li^{1

3}, Xiao-Mei Shi^{1

2}, Xin-Yuan Sun^{1

2}, Zhuo Li¹, Yan Cheng^{1

3}

Affiliations

¹ Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China.
² Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.
³ Hunan Provincial Engineering Research Centre of Translational Medicine and Innovative Drug, Changsha, China.

Abstract

BRAF inhibitors are commonly used in targeted therapies for melanoma patients harboring BRAF^V600E mutant. Despite the benefit of vemurafenib therapy, acquired resistance during or after treatment remains a major obstacle in BRAF^V600E mutant melanoma. Here we found that RSK2 is overexpressed in melanoma cells and the high expression of RSK2 indicates poor overall survival (OS) in melanoma patients. Overexpression of RSK2 leads to vemurafenib resistance, and the deletion of RSK2 inhibits cell proliferation and sensitizes melanoma cells to vemurafenib. Mechanistically, RSK2 enhances the phosphorylation of FOXO1 by interacting with FOXO1 and promoting its subsequent degradation, leading to upregulation of cyclin D1 in melanoma cells. These results not only reveal the presence of a RSK2-FOXO1-cyclin D1 signaling pathway in melanoma, but also provide a potential therapeutic strategy to enhance the efficacy of vemurafenib against cancer.

Keywords: FoxO1; Rsk2; cyclin D1; melanoma; vemurafenib.