Involvement of nuclear receptor RZR/RORγ in melatonin-induced HIF-1α inactivation in SGC-7901 human gastric cancer cells.
The melatonin nuclear receptor is an orphan member of the nuclear receptor superfamily RZR/ROR, which consists of three subtypes (α, β and γ), suggesting that immunomodulatory and antitumor effects through the intracellular action of melatonin depend on nuclear signaling. In the present study, the biological mechanisms of melatonin were elucidated in association with the RZR/RORγ pathway in SGC-7901 human gastric cancer cells under hypoxia. Melatonin suppressed the activity of RZR/RORγ and SUMO-specific protease 1 (SENP1) signaling pathway, which is essential for stabilization of hypoxia‑inducible factor-1α (HIF‑1α) during hypoxia. Furthermore, melatonin inhibited the stability of HIF-1α in a time- and conce-ntration-dependent manner in SGC-7901 human gastric cancer cells during hypoxia. Consistently, siRNA-RZR/RORγ effectively blocked the expression of SENP1, HIF-1α and vascular endothelial growth factor (VEGF) production in SGC-7901 cells under hypoxia, suggesting the role of nuclear receptor RZR/RORγ in melatonin-inhibited HIF-1α and VEGF accumulation. Moreover, siRNA RZR/RORγ obviously antagonized to inhibit the action of the gastric cancer cell proliferation by melatonin. Our findings suggest that melatonin suppresses HIF-1α accumulation and VEGF generation via inhibition of melatonin nuclear receptor RZR/RORγ in SGC-7901 cells under hypoxia.
The Chemotherapy Department of The First Affiliated Hospital, Fujian Medical University, Fuzhou, Fujian, P.R. China.
Ri-Xiong
RX
Wang
Department of Human Anatomy, Histology and Embryology, Fujian Medical University, Fuzhou, Fujian, P.R. China.
Hui
H
Liu
Department of Human Anatomy, Histology and Embryology, Fujian Medical University, Fuzhou, Fujian, P.R. China.
Li
L
Xu
Department of Human Anatomy, Histology and Embryology, Fujian Medical University, Fuzhou, Fujian, P.R. China.
Hui
H
Zhang
Department of Human Anatomy, Histology and Embryology, Fujian Medical University, Fuzhou, Fujian, P.R. China.
Rui-Xiang
RX
Zhou
D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D003546:Cysteine Endopeptidases; D010450:Endopeptidases / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008550:Melatonin / Q000502:physiology*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D042461:Vascular Endothelial Growth Factor A; D010450:Endopeptidases; C404512:SENP1 protein, human; D003546:Cysteine Endopeptidases; D008550:Melatonin