Loss of myosin light chain kinase induces the cellular senescence-associated secretory phenotype to promote breast epithelial cell migration

Abstract Overexpression 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. In breast cancer cells, myosin light chain kinase (MLCK) is notably downregulated. Our study demonstrates that MLCK depletion enhances cell migration through senescence-associated secretory phenotypes in breast epithelial cells. The reduction of MLCK results in an increase in p21Cip1 mRNA transcripts and protein expression, which is regulated by p53. Subsequently, p21Cip1 promotes the secretion of soluble ICAM-1, IL-1α, IL-6, and IL-8, thereby enhancing collective cell migration in MLCK-depleted cells. Interestingly, AKT-mammalian target of rapamycin (mTOR) signaling pathway also supports p21Cip1 induction and regulates cell migration in MLCK-depleted cells. These findings provide new mechanistic insights into the role of MLCK in cellular senescence and cancer progression.