Possible Involvement of the Nuclear RZR/ROR-Alpha Receptor in the Antitumor Action of Melatonin on Murine Colon 38 Cancer

Experimental evidence has shown that melatonin (MLT) may act through both membrane and nuclear receptors. Moreover, it was proposed that the nuclear MLT receptor is identical with nuclear orphan receptors called RZR/ROR. Our earlier results suggest that the antitumor action of MLT depends mainly on nuclear signaling. In the present study, we investigated whether CGP 55644 (an antagonist of the nuclear RZR/RORalpha receptor) changes the oncostatic effects of MLT on murine Colon 38 cancer. The experiment was performed on adult male B6D2F1 mice. MLT or CGP were given either alone or combined during 10 days, and cell proliferation, apoptosis and the proliferation/apoptosis (P/A) ratio were determined. Cell proliferation was assessed by incorporation of bromodeoxyuridine into tumor cell nuclei (labeling index - LI). The number of apoptotic cells using the TUNEL method was considered as an index of apoptosis. It was found that MLT inhibited cell proliferation. Addition of CGP to MLT diminished the antiproliferative effect of MLT. Moreover, MLT increased the apoptotic index, but CGP decreased apoptosis. In addition, CGP given together with MLT blocked its proapoptotic effect. Given alone, MLT strongly lowered the P/A ratio, and addition of CGP to MLT abolished the effect of MLT on the P/A ratio. Based on our data, we conclude that nuclear RZR/RORalpha receptors participate in the oncostatic action of MLT.