Inhibition of ERK5 Elicits Cellular Senescence in Melanoma via the Cyclin-Dependent Kinase Inhibitor p21

Abstract

Melanoma is the deadliest skin cancer with a very poor prognosis in advanced stages. Although targeted and immune therapies have improved survival, not all patients benefit from these treatments. The mitogen-activated protein kinase ERK5 supports the growth of melanoma cells in vitro and in vivo. However, ERK5 inhibition results in cell-cycle arrest rather than appreciable apoptosis. To clarify the role of ERK5 in melanoma growth, we performed transcriptomic analyses following ERK5 knockdown in melanoma cells expressing BRAFV600E and found that cellular senescence was among the most affected processes. In melanoma cells expressing either wild-type or mutant (V600E) BRAF, both genetic and pharmacologic inhibition of ERK5 elicited cellular senescence, as observed by a marked increase in senescence-associated β-galactosidase activity and p21 expression. In addition, depletion of ERK5 from melanoma cells resulted in increased levels of CXCL1, CXCL8, and CCL20, proteins typically involved in the senescence-associated secretory phenotype. Knockdown of p21 suppressed the induction of cellular senescence by ERK5 blockade, pointing to p21 as a key mediator of this process. In vivo, ERK5 knockdown or inhibition with XMD8–92 in melanoma xenografts promoted cellular senescence. Based on these results, small-molecule compounds targeting ERK5 constitute a rational series of prosenescence drugs that may be exploited for melanoma treatment. Significance: This study shows that targeting ERK5 induces p21-mediated cellular senescence in melanoma, identifying a prosenescence effect of ERK5 inhibitors that may be exploited for melanoma treatment.

Clinical Significance and Regulation of ERK5 Expression and Function in Cancer

“…However, recent findings showed that, in melanoma samples, mutated BRAF positively regulates activation of ERK5 that was highly correlated with melanoma proliferation by in vitro and in vivo studies [ 87 ]. Lately, Tubita et al [ 88 ] observed a blockade in the cell cycle progression in ERK5 knockdown in BRAF-mutated melanoma cells linked to the activation of cellular senescence mechanisms which includes the involvement of CDK inhibitors. Additionally, NRAS -mutant melanoma cells showed a proliferative advantage when, in response to MEK inhibitors treatment, expressed high levels of active ERK5 and the high rate of ERK5 was correlated with nuclear localization of the stem-like factor KLF2 [ 43 ].…”

Exploring the pharmacological mechanisms of icaritin against nasopharyngeal carcinoma via network pharmacology and experimental validation

“…Previous flow cytometry results have shown that icaritin causes cellular S-phase arrest. The cell cycle regulates cell differentiation and proliferation and is also closely related to cellular senescence (Shi et al, 2021;Tubita et al, 2022). The induction of cellular senescence is one of the mechanisms of anti-tumor drugs.…”

Immunomodulatory Properties of PI3K/AKT/mTOR and MAPK/MEK/ERK Inhibition Augment Response to Immune Checkpoint Blockade in Melanoma and Triple-Negative Breast Cancer

“…Another potential pathway of interest to combat intrinsic or acquired resistance to immunotherapy and BRAF/MEK1/2 inhibitors is the MEK/ERK5 pathway (Figure 2). Genetic and pharmacological inhibition of ERK5 in melanoma cells leads to irreversible cellular senescence mediated by p21 and suppresses resistance to BRAF and MEK1/2 inhibition in vitro [62,63]. In TNBC, targeting ERK5 inhibits cell cycle progression, promotes apoptosis, and enhances tumor cell sensitivity to chemotherapy [64].…”