Down-regulation of myosin light chain kinase (MLCK) contributes to breast cancer invasion and metastasis
The research group of Professor David Helfman in the Department of Biological Sciences at KAIST, has produced another important work focusing on cancer cell biology. By studying what happens when a particular protein kinase, called myosin light chain kinase (MLCK), is down-regulated they observed that critical changes occur at the cellular level resulting in increased cell migration and invasion which might facilitate the spread of cancer. By contrast inhibition of the catalytic function using pharmacological agents caused inhibition of cell motility. Thus, MLCK was found to have a previously uncharacterized function independent of its well-characterized catalytic role. The findings provide new insights into how the loss of this kinase in breast cancer patients is correlated with a poor prognosis. Helfman is a career cancer biologist and has been at KAIST since moving from the University of Miami in 2009, where he was the founding director of a graduate program in cancer biology. Before that, he was a professor at Cold Spring Harbor Laboratory, NY.
Breast cancer is the number one cause of death among South Korean women between the ages of 25-49. In South Korea, more than 11,000 new cases of breast cancer are diagnosed per year and the incidence is increasing by 10% each year. Breast cancer is among the most expensive forms of cancer to treat. Thus it is a great economic burden to the nation. On a global scale, breast cancer is almost a major problem in western countries and it is estimated that 1 in 8 women will get breast cancer in their lifetime. For example, over 200,000 new cases of breast cancer are diagnosed annually in the United States. Despite the ability of chemotherapy and radiation therapy to reduce the risk of breast cancer recurrence and to prolong survival, there is a continued need for more effective and less toxic therapies. In addition, it is estimated that metastasis is the cause of death in 90% of cancer patients and not the primary tumor. Thus understanding the process of metastasis is essential for the development of effective therapies.
The research group of David Helfman in the Department of Biological Sciences at KAIST (firstname.lastname@example.org), is studying breast cancer. Recently a member of his group, Dayoung Kim, published in Oncogene (a Nature Group publication). In this current technical article, they interrogated the role of myosin light chain kinase (MLCK) in breast cancer.
Decreased expression of MLCK is associated with various human cancers but little is known about how loss of MLCK affects the properties of tumor cells. The authors hypothesized that down-regulation of MLCK might be one important target during cancer progression. First, they showed that most breast cancer cell lines have down-regulated MLCK expression. Importantly, following siRNA-mediated down-regulation of MLCK they find that loss of MLCK in breast epithelial cells leads to increased cell migration and invasive behaviors. Interestingly, down-regulation of MLCK, and not pharmacological inhibition of MLCK, resulted in increased cell migration and invasion by reorganization of the actin cytoskeleton, cell-cell contacts, and cell-matrix adhesions. MLCK loss in breast epithelial cells induced increased expression and activation of EGFR with activating MEK-ERK and JNK-Paxillin pathways, and these signaling pathways mediated the phenotypic changes associated with down-regulation of MLCK. Finally, Oncomine, the human cancer database reveals decreased levels of MLCK expression in invasive breast carcinoma in comparison to carcinoma in situ, and the less MLCK expression in metastatic breast tumors than non-metastatic tumors.
This is the first report that kinase and non-kinase functions of MLCK have distinct roles in cell migration and invasion, and related signaling pathways in human epithelial cells. In addition, the studies demonstrated that MLCK is involved in crosstalk between EGFR and adhesion molecules, E-cadherin and integrins. Collectively, these findings suggest that MLCK can function as a tumor suppressor and loss of MLCK could contribute to the metastatic properties of tumor cells.
Contributors of this article are Dayoung Kim who was a graduate student in the Helfman laboratory and is now a postdoctoral fellow.
The full article of this journal is available from:
D Y Kim, and D M Helfman “Loss of MLCK leads to disruption of cell–cell adhesion and invasive behavior of breast epithelial cells via increased expression of EGFR and ERK/JNK signaling” Oncogene advance online publication 15 February 2016; doi: 10.1038/onc.2015.508.
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