Purpose
To explore whether melatonin affect the progression of cell cycle and exert anticancer activities via the modulation of CDK4 in NSCLC .
Methods
Cells treated with melatonin were used for assessing the anticancer effect of melatonin. Cells transfected with lentivirus for CDK4 upregulation or downregulation was constructed to evaluate the role of CDK4 in melatonin-induced anticancer effect. The protein and mRNA level of CDK4, PCNA and Bax were detected by western blotting and qRT-PCR. The application of flow cytometry was used for analyzing the distribution of cell cycle and apoptosis. Animal model of subcutaneous tumor was constructed and used for further study in vivo.
Results
We found that melatonin inhibited cell viability, colony formation, downregulated the expression of CDK4 and PCNA while upregulated the level of Bax. Besides, melatonin decreased the phosphorylation of ERK. Importantly, inhibition of ERK activation by PD98059 particapated in melatonin-induced downregulation of CDK4. Furthermore, melatonin led to G1 arrest and cell apoptosis. CDK4 knockdown enhanced melatonin-induced cell cycle arrest while CDK4 overexpression reversed the effect. Additionally, the animal experiment showed that melatonin decreased the level of CDK4 and inhibited tumor growth. However, the anti-tumor effect of melatonin was reversed by CDK4 overexpression.
Conclusion
Taken together, CDK4 involved in anti-cancer activities of melatonin. Melatonin led to G1 arrest, blocked G1-to-S transition, as a result, inhibited cell proliferation and accelerates apoptosis via suppressing CDK4 signaling. Targeting CDK4 inhibition and combining it with melatonin has protential to be a novel strategy for NSCLC.
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