The Mechanism Of Melatonin Inhibiting Alveolar Rhabdomyosarcoma

Melatonin is a small molecule of indole hormone produced by the pineal gland in the brain and other tissues.As an endogenous substance,it has numerous biological functions that modulate circadian rhythms by oxidative stress protection and eliminate free radicals.In addition,melatonin plays a role in tumor cell growth as well as counteracts chemoresistance in cancer.Rhabdomyosarcoma(RMS)is a malignant tumor of striated muscle differentiated mesenchymal cells and is common soft tissue sarcomas in children.The current classification defines two types including embryonal(eRMS)and alveolar(aRMS),whereas aRMS is more aggressive and characterized by a poorer prognosis than eRMS.In former study,dysregulation of some signaling pathways play an important role in different types of cancer.Sonic hedgehog(Shh)signaling plays an essential role in embryonic development and is critical for maintenance of tissue polarity.It has also been shown that Shh is association with the process of tumorigenesis,such as basal cell carcinoma and medulloblastoma.As a dominate member of the Shh signaling pathway,aberrant expression of Gli1 is often directly related to tumor cell proliferation and survival.In our study,two RMS cell lines(RD and RH30)were treated by MT and the cell growth of RH30 was effectively reduced by promoting cell apoptosis.Meanwhile,the ability of migration,invasion and tumorigenicity of RH30 were significantly inhibited after MT supplement comparing with RD.In order to explore the mechanism that MT affects RH30 by modulating Glil,we investigated Gli1 expression in RH30 and found that MT can down-regulate Glil in RH30.Further data confirmed that the decrease of RH30 cell proliferation can also be restrained by GANT61(Glil inhibitor).Ubiquitination modification,as a major post-translational modification pathway,regulates the proteasome degradation of transcription factor Glil in Shh signaling,and our results showed increase of the ubiquitinated Glil after MT treatment.From this investigation we conclude that MT can inhibit the malignant proliferation of RH30 cells by regulating the ubiquitination of Gli1 and promoting the degradation of Glil.