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ROCK inhibition modulates the senescence‐associated secretory phenotype (SASP) in oral keratinocytes
FEBS Open Bio ( IF 2.6 ) Pub Date : 2020-10-23 , DOI: 10.1002/2211-5463.13012
Sven Niklander 1, 2 , Deepti Bandaru 1 , Daniel W Lambert 1 , Keith D Hunter 1
Affiliation  

Senescent cells accumulate in different organs and develop a senescence‐associated secretory phenotype (SASP), associated with the development of age‐related pathologies. The constitution of the SASP varies among cell types and with the method of senescence induction; nevertheless, there is substantial overlap among SASPs, especially the presence of pro‐inflammatory cytokines such as IL‐1β, IL‐1α, IL‐6 and IL‐8. These cytokines are highly conserved among SASPs and are implicated in the development of several cancers. Here, we report that ROCK inhibition by Y‐27632 reduces levels of IL‐1α, IL‐1β, IL‐6 and IL‐8 secreted by senescent normal and dysplastic oral keratinocytes without affecting the permanent cell growth arrest. The data indicate some inflammatory genes downregulated by Y‐27632 remain downregulated even after repeated passage in the absence of Y‐27632. We propose ROCK kinase inhibition as a novel alternative to current strategies to modulate the inflammatory components of the SASP, without compromising the permanent cell growth arrest. This observation potentially has wide clinical applications, given the involvement of senescence in cancer and a wide range of age‐related disease. It also suggests care should be exercised when using Y‐27632 to facilitate cell expansion of primary cells, as its effects on gene expression are not entirely reversible.

中文翻译:

ROCK抑制调节口腔角质形成细胞中的衰老相关分泌表型(SASP)

衰老细胞在不同器官中积累并形成衰老相关分泌表型 (SASP),这与年龄相关病理的发展有关。SASP的构成因细胞类型和衰老诱导方法而异;尽管如此,SASP 之间存在大量重叠,尤其是促炎细胞因子的存在,如 IL-1β、IL-1α、IL-6 和 IL-8。这些细胞因子在 SASP 中高度保守,并且与多种癌症的发展有关。在这里,我们报告 Y-27632 的 ROCK 抑制降低了衰老的正常和发育不良口腔角质形成细胞分泌的 IL-1α、IL-1β、IL-6 和 IL-8 的水平,而不影响永久性细胞生长停滞。数据表明一些被 Y-27632 下调的炎症基因即使在没有 Y-27632 的情况下重复传代后仍保持下调。我们建议将 ROCK 激酶抑制作为当前调节 SASP 炎症成分的策略的新替代方案,同时不会影响永久性细胞生长停滞。鉴于衰老涉及癌症和广泛的年龄相关疾病,这一观察结果可能具有广泛的临床应用。它还建议在使用 Y-27632 促进原代细胞的细胞扩增时应小心谨慎,因为它对基因表达的影响并非完全可逆。鉴于衰老涉及癌症和广泛的年龄相关疾病,这一观察结果可能具有广泛的临床应用。它还建议在使用 Y-27632 促进原代细胞的细胞扩增时应小心谨慎,因为它对基因表达的影响并非完全可逆。鉴于衰老涉及癌症和广泛的年龄相关疾病,这一观察结果可能具有广泛的临床应用。它还建议在使用 Y-27632 促进原代细胞的细胞扩增时应小心谨慎,因为它对基因表达的影响并非完全可逆。
更新日期:2020-12-03
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