1. Loss of myosin light chain kinase induces the cellular senescence associated secretory phenotype to promote breast epithelial cell migration.
- Author
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Kim D, Cooper JA, and Helfman DM
- Subjects
- Humans, Female, TOR Serine-Threonine Kinases metabolism, Tumor Suppressor Protein p53 metabolism, Tumor Suppressor Protein p53 genetics, Senescence-Associated Secretory Phenotype, Proto-Oncogene Proteins c-akt metabolism, Cellular Senescence, Signal Transduction, Intercellular Adhesion Molecule-1 metabolism, Intercellular Adhesion Molecule-1 genetics, Breast metabolism, Breast pathology, Breast Neoplasms pathology, Breast Neoplasms metabolism, Breast Neoplasms genetics, Myosin-Light-Chain Kinase metabolism, Myosin-Light-Chain Kinase genetics, Cell Movement, Epithelial Cells metabolism, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Cyclin-Dependent Kinase Inhibitor p21 genetics
- Abstract
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
Cip1 expression, dependent on p53 and the AKT-mammalian target of rapamycin pathway. Subsequently, p21Cip1 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., (© 2024. The Author(s).)- Published
- 2024
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