title: Melatonin enhances arsenic trioxide-induced cell death via sustained upregulation of Redd1 expression in breast cancer cells.
abstract: Melatonin is implicated in various physiological functions, including anticancer activity. However, the mechanism(s) of its anticancer activity is not well understood. In the present study, we investigated the combined effects of melatonin and arsenic trioxide (ATO) on cell death in human breast cancer cells. Melatonin enhanced the ATO-induced apoptotic cell death via changes in the protein levels of Survivin, Bcl-2, and Bax, thus affecting cytochrome c release from the mitochondria to the cytosol. Interestingly, we found that the cell death induced by co-treatment with melatonin and ATO was mediated by sustained upregulation of Redd1, which was associated with increased production of reactive oxygen species (ROS). Combined treatment with melatonin and ATO induced the phosphorylation of JNK and p38 MAP kinase downstream from Redd1 expression. Rapamycin and S6K1 siRNA enhanced, while activation of mTORC1 by transfection with TSC2 siRNA suppressed the cell death induced by melatonin and ATO treatment. Taken together, our findings suggest that melatonin enhances ATO-induced apoptotic cell death via sustained upregulation of Redd1 expression and inhibition of mTORC1 upstream of the activation of the p38/JNK pathways in human breast cancer cells.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 139-706, Republic of Korea.
authors.forename: Sun-Mi
authors.initials: SM
authors.lastname: Yun
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 139-706, Republic of Korea; KIRAMS Radiation Biobank, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 139-709, Republic of Korea.
authors.forename: Sang Hyeok
authors.initials: SH
authors.lastname: Woo
authors.affiliation: Department of Radiation Oncology, College of Medicine, Yonsei University, Seoul 120-752, Republic of Korea.
authors.forename: Sang Taek
authors.initials: ST
authors.lastname: Oh
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 139-706, Republic of Korea.
authors.forename: Sung-Eun
authors.initials: SE
authors.lastname: Hong
authors.affiliation: Department of Microbiological Engineering, Kon-Kuk University, 120 Neungdong-ro, Gwangjin-gu, Seoul 143-701, Republic of Korea.
authors.forename: Tae-Boo
authors.initials: TB
authors.lastname: Choe
authors.affiliation: Department of Pharmacology, Seoul National University College of Medicine, 103 Daehangno, Jongno-gu Seoul 110-799, Republic of Korea.
authors.forename: Sang-Kyu
authors.initials: SK
authors.lastname: Ye
authors.affiliation: Department of Surgery, Seoul National University Bundang Hospital, 82 Gumi-ro, 173 Beon-gil, Bundang-gu, Seongnam-si, Gyenggi-do 463-707, Republic of Korea.
authors.forename: Eun-Kyu
authors.initials: EK
authors.lastname: Kim
authors.affiliation: Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea.
authors.forename: Min Ki
authors.initials: MK
authors.lastname: Seong
authors.affiliation: Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea.
authors.forename: Hyun-A
authors.initials: HA
authors.lastname: Kim
authors.affiliation: Department of Surgery, Korea Cancer Center Hospital, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-706, Republic of Korea.
authors.forename: Woo Chul
authors.initials: WC
authors.lastname: Noh
authors.affiliation: KIRAMS Radiation Biobank, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 139-709, Republic of Korea.
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Lee
authors.affiliation: KIRAMS Radiation Biobank, Korea Institute of Radiological & Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 139-709, Republic of Korea.
authors.forename: Hyeon-Ok
authors.initials: HO
authors.lastname: Jin
authors.affiliation: Department of Radiation Oncology, College of Medicine, Yonsei University, Seoul 120-752, Republic of Korea. Electronic address: yhlee87@yuhs.ac.
authors.forename: Yun-Han
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, 75 Nowon-ro, Nowon-gu, Seoul 139-706, Republic of Korea. Electronic address: parkic@kirams.re.kr.
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D016923:Cell Death; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008550:Melatonin / Q000494:pharmacology*; D010087:Oxides / Q000494:pharmacology*; D014157:Transcription Factors / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; C469991:DDIT4 protein, human; D010087:Oxides; D014157:Transcription Factors; D008550:Melatonin; D000077237:Arsenic Trioxide
keywords: Apoptotic cell death; Arsenic trioxide; Melatonin; Redd1; mTORC1