title: Human transporters, PEPT1/2, facilitate melatonin transportation into mitochondria of cancer cells: An implication of the therapeutic potential.
abstract: 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 PEPT1/2 was attributed to their low binding energy and suitable binding conformation in which melatonin was embedded in the active site of PEPT1/2 and fitted well with the cavity in three-dimensional space. PEPT1/2 transporters play a pivotal role in melatonin uptake in cells. Melatonin's membrane transportation via PEPT1/2 renders its oncostatic effect in malignant cells. For the first time, PEPT1/2 were identified to localize in the mitochondrial membrane of human cancer cell lines of PC3 and U118. PEPT1/2 facilitated the transportation of melatonin into mitochondria. Melatonin accumulation in mitochondria induced apoptosis of PC3 and U118 cells. Thus, PEPT1/2 can potentially be used as a cancer cell-targeted melatonin delivery system to improve the therapeutic effects of melatonin in cancer treatment.
authors.affiliation: Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Xiaokui
authors.initials: X
authors.lastname: Huo
authors.affiliation: Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Zhenlong
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Yulin
authors.initials: Y
authors.lastname: Peng
authors.affiliation: Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM, Guangdong Pharmaceutical University, Guangdong, China.
authors.forename: Shumei
authors.initials: S
authors.lastname: Wang
authors.affiliation: Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Shengnan
authors.initials: S
authors.lastname: Feng
authors.affiliation: Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Shouji
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Xiangge
authors.initials: X
authors.lastname: Tian
authors.affiliation: Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Chengpeng
authors.initials: C
authors.lastname: Sun
authors.affiliation: Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Kexin
authors.initials: K
authors.lastname: Liu
authors.affiliation: Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.
authors.forename: Sa
authors.initials: S
authors.lastname: Deng
authors.affiliation: Key Laboratory of Pharmacokinetic and Drug Transport of Liaoning, College of Pharmacy, Academy of Integrative Medicine, Dalian Medical University, Dalian, China.|Key Laboratory of Digital Quality Evaluation of Chinese Materia Medica of State Administration of TCM, Guangdong Pharmaceutical University, Guangdong, China.
authors.forename: Xiaochi
authors.identifier: http://orcid.org/0000-0003-4397-537X
authors.initials: X
authors.lastname: Ma
mesh_terms: D015153:Blotting, Western; D018938:Caco-2 Cells; D002460:Cell Line; D002853:Chromatography, Liquid; D005434:Flow Cytometry; D006367:HeLa Cells; D006801:Humans; D008550:Melatonin / Q000378:metabolism*; D053078:Membrane Potential, Mitochondrial / Q000235:genetics / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism*; D000074011:Peptide Transporter 1; D017382:Reactive Oxygen Species / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D053719:Tandem Mass Spectrometry
chemical_list: D000074011:Peptide Transporter 1; D017382:Reactive Oxygen Species; D027981:Symporters; C093694:hydrogen-coupled oligopeptide transporter PepT2; D008550:Melatonin
keywords: PEPT1/2; apoptosis; cancer; melatonin; mitochondria; transporters