Loss of myosin light chain kinase induces the cellular senescence associated secretory phenotype to promote breast epithelial cell migration
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<sup>Cip1</sup> expression, dependent on p53 and the AKT-mammalian target of rapamycin pathway. Subsequently, p21<sup>Cip1</sup> 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.
Authors
- David M. Helfman
- Jonathan A. Cooper (ORCID: https://orcid.org/0000-0002-8626-7827)
- Dayoung Kim (ORCID: https://orcid.org/0009-0009-5836-0758)
Institutions
- Cape Town HVTN Immunology Laboratory / Hutchinson Centre Research Institute of South Africa (ZA)
- Korea Advanced Institute of Science and Technology (KR)
- Fred Hutch Cancer Center (US)
Publication Details
- Journal
- Scientific Reports
- Published
- 2024-10-28
- DOI
- https://doi.org/10.1038/s41598-024-76868-y
- Citations
- 5
- Primary Topic
- Telomeres, Telomerase, and Senescence
- Type
- article
- Field-Weighted Citation Impact
- 1.63
Funders
- Fred Hutchinson Cancer Research Center
- National Research Foundation
- National Research Foundation of Korea
- Korea Advanced Institute of Science and Technology
- Ministry of Science and ICT, South Korea