Inhibition of ERK5 Elicits Cellular Senescence in Melanoma via the Cyclin-Dependent Kinase Inhibitor p21.
Inhibition of ERK5 Elicits Cellular Senescence in Melanoma via the Cyclin-Dependent Kinase Inhibitor p21.
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DOI：
10.1158/0008-5472.can-21-0993
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发表时间：
2022-02-01
期刊：
影响因子：
11.2
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中科院分区：
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这项研究表明，针对 ERK5 会诱导黑色素瘤中 p21 介导的细胞衰老，从而确定 ERK5 抑制剂的衰老作用，可用于黑色素瘤的治疗。黑色素瘤是最致命的皮肤癌，晚期预后非常差。尽管靶向治疗和免疫治疗提高了生存率，但并非所有患者都能从这些治疗中受益。丝裂原激活蛋白激酶 ERK5 支持体外和体内黑色素瘤细胞的生长。然而，ERK5 抑制会导致细胞周期停滞，而不是明显的细胞凋亡。为了阐明 ERK5 在黑色素瘤生长中的作用，我们在表达 BRAFV600E 的黑色素瘤细胞中敲低 ERK5 后进行了转录组分析，发现细胞衰老是受影响最大的过程之一。在表达野生型或突变型 (V600E) BRAF 的黑色素瘤细胞中，ERK5 的遗传和药理学抑制都会引发细胞衰老，如衰老相关 β-半乳糖苷酶活性和 p21 表达显着增加所观察到的。此外，黑色素瘤细胞中 ERK5 的耗竭导致 CXCL1、CXCL8 和 CCL20 水平升高，这些蛋白质通常与衰老相关的分泌表型有关。 p21 的敲除抑制了 ERK5 阻断诱导的细胞衰老，表明 p21 是该过程的关键介质。在体内，黑色素瘤异种移植物中 ERK5 敲低或 XMD8-92 抑制可促进细胞衰老。基于这些结果，靶向 ERK5 的小分子化合物构成了一系列合理的抗衰老药物，可用于黑色素瘤的治疗。这项研究表明，针对 ERK5 会诱导黑色素瘤中 p21 介导的细胞衰老，从而确定 ERK5 抑制剂的衰老作用，可用于黑色素瘤的治疗。
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. 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. 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.