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Human transporters, PEPT 1/2, facilitate melatonin transportation into mitochondria of cancer cells: An implication of the therapeutic potential
Author(s) -
Huo Xiaokui,
Wang Chao,
Yu Zhenlong,
Peng Yulin,
Wang Shumei,
Feng Shengnan,
Zhang Shouji,
Tian Xiangge,
Sun Chengpeng,
Liu Kexin,
Deng Sa,
Ma Xiaochi
Publication year - 2017
Publication title -
journal of pineal research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.881
H-Index - 131
eISSN - 1600-079X
pISSN - 0742-3098
DOI - 10.1111/jpi.12390
Subject(s) - melatonin , cancer cell , intracellular , mitochondrion , biology , transporter , microbiology and biotechnology , receptor , apoptosis , melatonin receptor , biochemistry , chemistry , endocrinology , cancer , gene , genetics
Melatonin is present in virtually all organisms from bacteria to mammals, and it exhibits a broad spectrum of biological functions, including synchronization of circadian rhythms and oncostatic activity. Several functions of melatonin are mediated by its membrane receptors, but others are receptor‐independent. For the latter, melatonin is required to penetrate membrane and enters intracellular compartments. However, the mechanism by which melatonin enters cells remains debatable. In this study, it was identified that melatonin and its sulfation metabolites were the substrates of oligopeptide transporter ( PEPT ) 1/2 and organic anion transporter ( OAT ) 3, respectively. The docking analysis showed that the binding of melatonin to PEPT 1/2 was attributed to their low binding energy and suitable binding conformation in which melatonin was embedded in the active site of PEPT 1/2 and fitted well with the cavity in three‐dimensional space. PEPT 1/2 transporters play a pivotal role in melatonin uptake in cells. Melatonin's membrane transportation via PEPT 1/2 renders its oncostatic effect in malignant cells. For the first time, PEPT 1/2 were identified to localize in the mitochondrial membrane of human cancer cell lines of PC 3 and U118. PEPT 1/2 facilitated the transportation of melatonin into mitochondria. Melatonin accumulation in mitochondria induced apoptosis of PC 3 and U118 cells. Thus, PEPT 1/2 can potentially be used as a cancer cell‐targeted melatonin delivery system to improve the therapeutic effects of melatonin in cancer treatment.