title: 1α,25(OH)2D3 Analog, MART-10, Inhibits Neuroendocrine Tumor Cell Growth Through Induction of G0/G1 Cell-cycle Arrest and Apoptosis.
abstract: BACKGROUND
  Neuroendocrine tumors (NETs) are the second most common digestive malignancy. For advanced NETs, survival is not satisfactory. Vitamin D has emerged as a promising anticancer drug.
  
  
  METHODS
  Cell proliferation assay, western blot, flow cytometry, and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays were applied.
  
  
  RESULTS
  We demonstrated that RIN-m cells, neuroendocrine tumor cells, expressed vitamin D receptor (VDR) and VDR expression increased with increasing exposure to 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] or MART-10, a 1α,25(OH)2D3 analog. MART-10 had anti-growth effect on RIN-m cells comparable to those of 1α,25(OH)2D3 The growth inhibition of both drugs was mediated by induction of cell-cycle arrest at G0/G1 phase and apoptosis. Western blot assay further revealed that this G0/G1 arrest was due to the up-regulation of p27 and down-regulation of cyclin dependent kinase 4 (CDK4), with MART-10 also reducing CDK6. Apoptosis induction was further supported by increased cleaved caspase-3 expression after treatment.
  
  
  CONCLUSIONS
  MART-10 appears to be a promising regimen for NET treatment.
authors.affiliation: General Surgery Department, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, R.O.C. Zebrafish Center, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, R.O.C.
authors.forename: Kun-Chun
authors.initials: KC
authors.lastname: Chiang
authors.affiliation: Department of General Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, R.O.C.
authors.forename: Chun-Nan
authors.initials: CN
authors.lastname: Yeh
authors.affiliation: Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, R.O.C.
authors.forename: Jong-Hwei S
authors.initials: JH
authors.lastname: Pang
authors.affiliation: Department of General Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, R.O.C.
authors.forename: Jun-Te
authors.initials: JT
authors.lastname: Hsu
authors.affiliation: Department of General Surgery, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, R.O.C.
authors.forename: Ta-Sen
authors.initials: TS
authors.lastname: Yeh
authors.affiliation: Department of Gastroenterology, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, R.O.C.
authors.forename: Li-Wei
authors.initials: LW
authors.lastname: Chen
authors.affiliation: Department of Endocrinology and Metabolism, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, R.O.C.
authors.forename: Sheng-Fong
authors.initials: SF
authors.lastname: Kuo
authors.affiliation: Department of Gastroenterology, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, R.O.C.
authors.forename: Po-Jen
authors.initials: PJ
authors.lastname: Hsieh
authors.affiliation: Department of General Dentistry, Chang Gung Memorial Hospital, Chang Gung University, Keelung, Taiwan, R.O.C.
authors.forename: Yi-Chun
authors.initials: YC
authors.lastname: Pan
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Takano
authors.affiliation: Boston University School of Medicine, Boston, MA, U.S.A.
authors.forename: Tai C
authors.initials: TC
authors.lastname: Chen
authors.affiliation: Nursing School, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, R.O.C. akittaka@pharm.teikyo-u.ac.jp hhj143@mail.cgu.edu.tw thf@mail.cgu.edu.tw.
authors.forename: Tsui-Hsia
authors.initials: TH
authors.lastname: Feng
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, Sagamihara, Kanagawa, Japan akittaka@pharm.teikyo-u.ac.jp hhj143@mail.cgu.edu.tw thf@mail.cgu.edu.tw.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
authors.affiliation: Department of Urology, Chang Gung Memorial Hospital, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, R.O.C. Department of Anatomy, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, Taiwan, R.O.C. akittaka@pharm.teikyo-u.ac.jp hhj143@mail.cgu.edu.tw thf@mail.cgu.edu.tw.
authors.forename: Horng-Heng
authors.initials: HH
authors.lastname: Juang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002117:Calcitriol / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000494:pharmacology; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects*; D007340:Insulinoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018358:Neuroendocrine Tumors / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051381:Rats; D018167:Receptors, Calcitriol / Q000096:biosynthesis
chemical_list: C569618:19-nor-2-(3-hydroxypropyl)-1,25-dihydroxyvitamin D3; C493962:Cdkn1b protein, rat; D018167:Receptors, Calcitriol; D050760:Cyclin-Dependent Kinase Inhibitor p27; D002762:Cholecalciferol; C495903:Cdk4 protein, rat; D051358:Cyclin-Dependent Kinase 4; D002117:Calcitriol
keywords: 1α,25(OH)2D3; EMT; HNSCC; MART-10; metastasis; vitamin D