Basic Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA.
Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, South Korea.
Sci Rep. 2024 Oct 28;14(1):25786. doi: 10.1038/s41598-024-76868-y.
Overexpression or activation of oncogenes or loss of tumor-suppressor genes can induce cellular senescence as a defense mechanism against tumor development, thereby maintaining cellular homeostasis. However, cancer cells can circumvent this senescent state and continue to spread. Myosin light chain kinase (MLCK) is downregulated in many breast cancers. Here we report that downregulation of MLCK in normal breast epithelial cells induces a senescence-associated secretory phenotype and stimulates migration. The reduction of MLCK results in increased p21 expression, dependent on p53 and the AKT-mammalian target of rapamycin pathway. Subsequently, p21 promotes the secretion of soluble ICAM-1, IL-1α, IL-6 and IL-8, thereby enhancing collective cell migration in a non-cell-autonomous manner. These findings provide new mechanistic insights into the role of MLCK in cellular senescence and cancer progression.
癌基因的过表达或激活或肿瘤抑制基因的丢失会导致细胞衰老，作为一种防止肿瘤发生的防御机制，从而维持细胞的内稳态。然而，癌细胞可以逃避这种衰老状态并继续扩散。许多乳腺癌中肌球蛋白轻链激酶（MLCK）下调。在这里，我们报告在正常乳腺上皮细胞中下调 MLCK 会诱导与衰老相关的分泌表型并刺激迁移。MLCK 的减少导致 p21 表达增加，这依赖于 p53 和 AKT-雷帕霉素靶蛋白通路。随后，p21 促进可溶性 ICAM-1、IL-1α、IL-6 和 IL-8 的分泌，从而以非细胞自主的方式增强细胞的集体迁移。这些发现为 MLCK 在细胞衰老和癌症进展中的作用提供了新的机制见解。
