title: A synthetic chalcone, 2'-hydroxy-2,3,5'-trimethoxychalcone triggers unfolded protein response-mediated apoptosis in breast cancer cells.
abstract: The primary aim of this study was to find novel chemopreventive agents effective against breast cancer. Endoplasmic reticulum (ER) stress can induce apoptosis through the unfolded protein response (UPR). 2'-Hydroxy-2,3,5'-trimethoxychalcone (DK143) is a synthetic flavonoid derivative. The present study provides evidence supporting the role of the UPR in mediating the apoptotic effect of DK143. Treatment with DK143 triggered apoptosis through the activation of the caspase pathway in MDA-MB-231 breast cancer cells without affecting viability of MCF10A non-transformed breast epithelial cells. Further analysis revealed that DK143 produced reactive oxygen species (ROS) in MDA-MB-231 cells, but not in MCF10A cells, and upregulated the expression of ER stress sensors, including GRP78/BiP, IRE1α, CHOP, and Bim in MDA-MB-231 cells. In addition, UPR-related transcription factors, XBP-1 and CHOP, were activated by DK143. Moreover, silencing of IRE1α or CHOP by corresponding siRNA molecules attenuated DK143-induced apoptosis. Furthermore, DK143 suppressed mouse tumor growth in vivo. These results demonstrate that promoting ER stress in breast cancer cells via UPR induction might be a promising strategy for developing new chemotherapeutic or chemopreventive agents for breast cancer.
authors.affiliation: Department of Biological Sciences, College of Biological Science and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Da Hyun
authors.initials: DH
authors.lastname: Lee
authors.affiliation: Cancer and Metabolism Institute, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: You
authors.initials: Y
authors.lastname: Jung Jung
authors.affiliation: Department of Applied Chemistry, Dongduk Women's University, Seoul 02748, Republic of Korea.
authors.forename: Dongsoo
authors.initials: D
authors.lastname: Koh
authors.affiliation: Division of Bioscience and Biotechnology, BMIC, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Yoongho
authors.initials: Y
authors.lastname: Lim
authors.affiliation: Department of Biological Sciences, College of Biological Science and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea; Cancer and Metabolism Institute, Konkuk University, Seoul 05029, Republic of Korea.
authors.forename: Young Han
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, College of Biological Science and Biotechnology, Konkuk University, Seoul 05029, Republic of Korea; Cancer and Metabolism Institute, Konkuk University, Seoul 05029, Republic of Korea. Electronic address: shinsy@konkuk.ac.kr.
authors.forename: Soon Young
authors.initials: SY
authors.lastname: Shin
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D047188:Chalcones / Q000138:chemical synthesis / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000091342:Endoplasmic Reticulum Chaperone BiP; D004722:Endoribonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D008807:Mice, Inbred BALB C; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D056811:Unfolded Protein Response / Q000187:drug effects*
chemical_list: C000608811:2'-hydroxy-2,3,5'-trimethoxychalcone; D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D047188:Chalcones; C497249:DDIT3 protein, human; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D017382:Reactive Oxygen Species; D051742:Transcription Factor CHOP; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases; D020169:Caspases
keywords: 2'-Hydroxy-2,3,5'-trimethoxychalcone; Apoptosis; Breast cancer; Caspase; Reactive oxygen species; Unfolded protein response