title: Stronger proteasomal inhibition and higher CHOP induction are responsible for more effective induction of paraptosis by dimethoxycurcumin than curcumin.
abstract: Although curcumin suppresses the growth of a variety of cancer cells, its poor absorption and low systemic bioavailability have limited its translation into clinics as an anticancer agent. In this study, we show that dimethoxycurcumin (DMC), a methylated, more stable analog of curcumin, is significantly more potent than curcumin in inducing cell death and reducing the clonogenicity of malignant breast cancer cells. Furthermore, DMC reduces the tumor growth of xenografted MDA-MB 435S cells more strongly than curcumin. We found that DMC induces paraptosis accompanied by excessive dilation of mitochondria and the endoplasmic reticulum (ER); this is similar to curcumin, but a much lower concentration of DMC is required to induce this process. DMC inhibits the proteasomal activity more strongly than curcumin, possibly causing severe ER stress and contributing to the observed dilation. DMC treatment upregulates the protein levels of CCAAT-enhancer-binding protein homologous protein (CHOP) and Noxa, and the small interfering RNA-mediated suppression of CHOP, but not Noxa, markedly attenuates DMC-induced ER dilation and cell death. Interestingly, DMC does not affect the viability, proteasomal activity or CHOP protein levels of human mammary epithelial cells, suggesting that DMC effectively induces paraptosis selectively in breast cancer cells, while sparing normal cells. Taken together, these results suggest that DMC triggers a stronger proteasome inhibition and higher induction of CHOP compared with curcumin, giving it more potent anticancer effects on malignant breast cancer cells.
authors.affiliation: Department of Biochemistry, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: M J
authors.initials: MJ
authors.lastname: Yoon
authors.affiliation: Department of Biochemistry, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Y J
authors.initials: YJ
authors.lastname: Kang
authors.affiliation: Department of Biochemistry, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: J A
authors.initials: JA
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea.
authors.forename: I Y
authors.initials: IY
authors.lastname: Kim
authors.affiliation: 1] Department of Biochemistry, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea [2] Cancer Cell and Molecular Biology Branch, Division of Cancer Biology, Research Institute, National Cancer Center, Goyang, Korea.
authors.forename: M A
authors.initials: MA
authors.lastname: Kim
authors.affiliation: Department of Biomedical Sciences, Genomic Instability Research Center, Ajou University School of Medicine, Suwon, Korea.
authors.forename: Y S
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Molecular Science and Technology, Ajou University, Suwon, Korea.
authors.forename: B Y
authors.initials: BY
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: I A
authors.initials: IA
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan, Korea.
authors.forename: H S
authors.initials: HS
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Institute of Pharmaceutical Research and Development, Wonkwang University, Iksan, Korea.
authors.forename: S-A
authors.initials: SA
authors.lastname: Kim
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea.
authors.forename: A-R
authors.initials: AR
authors.lastname: Yoon
authors.affiliation: Department of Bioengineering, College of Engineering, Hanyang University, Seoul, Korea.
authors.forename: C-O
authors.initials: CO
authors.lastname: Yun
authors.affiliation: College of Pharmacy, Korea University, Sejong, Korea.
authors.forename: E-Y
authors.initials: EY
authors.lastname: Kim
authors.affiliation: College of Pharmacy, Korea University, Sejong, Korea.
authors.forename: K
authors.initials: K
authors.lastname: Lee
authors.affiliation: 1] Department of Biochemistry, Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Korea [2] Department of Biomedical Sciences, Genomic Instability Research Center, Ajou University School of Medicine, Suwon, Korea.
authors.forename: K S
authors.initials: KS
authors.lastname: Choi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects* / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; C497249:DDIT3 protein, human; C498702:PMAIP1 protein, human; D061988:Proteasome Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C521105:dimethoxycurcumin; D051742:Transcription Factor CHOP; D046988:Proteasome Endopeptidase Complex; D003474:Curcumin