title: Zoledronic acid-induced cytotoxicity through endoplasmic reticulum stress triggered REDD1-mTOR pathway in breast cancer cells.
abstract: BACKGROUND
  Zoledronic acid (ZOL) used for the prevention/treatment of osteopathic complications has been reported to have antitumor effects in breast cancer treatment. However, little is known about the exact molecular mechanisms for antitumor actions of ZOL. In this study, two breast cancer cell lines were used to investigate the antitumor efficacy of ZOL and the underlying molecular mechanisms.
  
  
  RESULTS
  The growth of two breast cancer cell lines was markedly decreased following treatment with ZOL. Compared with MCF-7 cells, MDA-MB-231 cells were more sensitive to ZOL treatment. Western blot analysis showed that the inhibitory effect of zoledronic acid on growth was related to the extent of inhibition of phosphorylated-protein kinase B (p-AKT), and phosphorylated-mammalian target of rapamycin (p-mTOR). Moreover, the expression of the stress-responsive protein regulated in development and DNA damage response 1 (REDD1), an inhibitor of mTOR, was induced markedly to various degrees in different breast cancer cell lines after ZOL treatment. Interestingly, by examining the upstream signaling pathway of REDD1, we found that ZOL can induce endoplasmic reticulum stress responses through activating the protein kinase R (PKR)-related ER kinase-eukaryotic initiation factor 2 alpha-CCAAT/enhancer binding protein homologous protein (PERK-eIF2α-CHOP) pathway.
  
  
  CONCLUSIONS
  Taken together, these results indicated that ZOL-induced cell death was caused by endoplasmic reticulum stress activating PERK-eIF2α-CHOP pathway to induce REDD1 expression and inhibit the mTOR pathway.
authors.affiliation: Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Taipei 112, Taiwan. Tel: +886 228757535, lmtseng@vghtpe.gov.tw.
authors.forename: Ya-Chun
authors.initials: YC
authors.lastname: Lan
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Chang
authors.forename: Ming-Ta
authors.initials: MT
authors.lastname: Sung
authors.forename: Pen-Hui
authors.initials: PH
authors.lastname: Yin
authors.forename: Chia-Chi
authors.initials: CC
authors.lastname: Hsu
authors.forename: Kuo-Chung
authors.initials: KC
authors.lastname: Wang
authors.forename: Hsin-Chen
authors.initials: HC
authors.lastname: Lee
authors.forename: Ling-Ming
authors.initials: LM
authors.lastname: Tseng
authors.forename: Chin-Wen
authors.initials: CW
authors.lastname: Chi
mesh_terms: D001483:Base Sequence; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division; D017931:DNA Primers; D004164:Diphosphonates / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D061986:MCF-7 Cells; D016133:Polymerase Chain Reaction; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D000077211:Zoledronic Acid
chemical_list: D050071:Bone Density Conservation Agents; C469991:DDIT4 protein, human; D017931:DNA Primers; D004164:Diphosphonates; D007093:Imidazoles; D014157:Transcription Factors; D000077211:Zoledronic Acid; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases
keywords: Breast cancer; MCF-7; MDA-MB-231 cells; REDD1; endoplasmic reticulum stress; mTOR; zoledronic acid