Melatonin decreases breast cancer metastasis by modulating Rho‐associated kinase protein‐1 expression

Abstract

The occurrence of metastasis, an important breast cancer prognostic factor, depends on cell migration/invasion mechanisms, which can be controlled by regulatory and effector molecules such as Rho-associated kinase protein (ROCK-1). Increased expression of this protein promotes tumor growth and metastasis, which can be restricted by ROCK-1 inhibitors. Melatonin has shown oncostatic, antimetastatic, and anti-angiogenic effects and can modulate ROCK-1 expression. Metastatic and nonmetastatic breast cancer cell lines were treated with melatonin as well as with specific ROCK-1 inhibitor (Y27632). Cell viability, cell migration/invasion, and ROCK-1 gene expression and protein expression were determined in vitro. In vivo lung metastasis study was performed using female athymic nude mice treated with either melatonin or Y27832 for 2 and 5 wk. The metastases were evaluated by X-ray computed tomography and single photon emission computed tomography (SPECT) and by immunohistochemistry for ROCK-1 and cytokeratin proteins. Melatonin and Y27632 treatments reduced cell viability and invasion/migration of both cell lines and decreased ROCK-1 gene expression in metastatic cells and protein expression in nonmetastatic cell line. The numbers of ‘hot’ spots (lung metastasis) identified by SPECT images were significantly lower in treated groups. ROCK-1 protein expression also was decreased in metastatic foci of treated groups. Melatonin has shown to be effective in controlling metastatic breast cancer in vitro and in vivo, not only via inhibition of the proliferation of tumor cells but also through direct antagonism of metastatic mechanism of cells rendered by ROCK-1 inhibition. When Y27632 was used, the effects were similar to those found with melatonin treatment.

Melatonin-induced KiSS1 expression inhibits triple-negative breast cancer cell invasiveness

“…This result was consistent with a previous study (28). Nevertheless, the mechanisms by which the inhibitory effect of melatonin is prolonged were not investigated.…”

“…However, previous studies have demonstrated that melatonin inhibited the metastatic abilities of MDA-MB-231 breast cancer cells by inhibiting either Rho-associated protein kinase 1 or p38 mitogen-activated protein kinases (31,32,46). Likewise, the results of the present study revealed that melatonin inhibited the invasiveness of triple-negative breast cancer cells with no effect on proliferation.…”

“…While it was revealed that melatonin regulates KiSS1 expression in the hypothalamus in the brain (26,27), an association between melatonin and KiSS1 in cancer has not been identified. While 1 mM melatonin treatment inhibited metastatic functions, including migration and invasion in triple-negative MDA-MB-231 breast cancer cell lines, the pharmacological concentration of melatonin also reduced the cell viability and caused apoptosis (28)(29)(30). In addition, physiological concentrations of melatonin only reduced the viabilities of less invasive, non-triple-negative breast cancer cells (28,31,32), which may be due to different MT1 expression levels in less or highly invasive breast cancer cells (33).…”

“…While 1 mM melatonin treatment inhibited metastatic functions, including migration and invasion in triple-negative MDA-MB-231 breast cancer cell lines, the pharmacological concentration of melatonin also reduced the cell viability and caused apoptosis (28)(29)(30). In addition, physiological concentrations of melatonin only reduced the viabilities of less invasive, non-triple-negative breast cancer cells (28,31,32), which may be due to different MT1 expression levels in less or highly invasive breast cancer cells (33). Therefore, whether melatonin directly inhibits the invasion of highly metastatic triple-negative breast cancer cells remains unclear.…”

Melatonin Attenuates Endothelial-to-Mesenchymal Transition of Glomerular Endothelial Cells via Regulating miR-497/ROCK in Diabetic Nephropathy

“…Suppressing ROCK2 expression reduces high-glucose-induced hyperpermeability in renal glomerular endothelia [18]. Previous studies also have shown that melatonin modulates ROCK1 and ROCK2 activation to inhibit cancer cell progression [19,20]. Yet, the relationship between melatonin and ROCK activation in diabetic nephropathy remains unknown.…”