title: Inhibition of vacuolar H+ ATPase enhances sensitivity to tamoxifen via up-regulation of CHOP in breast cancer cells.
abstract: Resistance of estrogen receptor-positive breast cancer cells to tamoxifen represents a major barrier to the successful treatment of breast cancer. In the present study, we found that vacuolar H+ ATPase (vATPase) inhibitors, bafilomycin A1 and concanamycin A, sensitize tamoxifen-induced cell death. siRNA targeting ATP6V0C, a 16-kDa hydrophobic proteolipid subunit of vATPase that plays a central role in H+ transport, markedly increased cell death induced by tamoxifen. Interestingly, bafilomycin A1 induced up-regulation of DR4/DR5 and CHOP. Knock-down of CHOP by siRNA suppressed the cell death induced by bafilomycin A1 and tamoxifen, suggesting that bafilomycin A1-mediated CHOP activation sensitizes to tamoxifen. In addition, we found that bafilomycin A1 enhances TRAIL-induced cell death in breast cancer cells. Furthermore, we showed that combination of vATPase inhibitors with tamoxifen also effectively induced cell death in HER2- and ERα-overexpressing breast cancer cells. Overall, our results demonstrate that inhibition of vATPase can potentiate the apoptotic effects of tamoxifen through up-regulation of CHOP.
authors.affiliation: Laboratory of Biospecimen Management & Research, Korea Institute of Radiological & Medical Sciences, 215-4 Gongneung-dong, Nowon-gu, Seoul 139-709, Republic of Korea.
authors.forename: Hyeon-Ok
authors.initials: HO
authors.lastname: Jin
authors.forename: Yun-Han
authors.initials: YH
authors.lastname: Lee
authors.forename: Hyun-Ah
authors.initials: HA
authors.lastname: Kim
authors.forename: Eun-Kyu
authors.initials: EK
authors.lastname: Kim
authors.forename: Woo Chul
authors.initials: WC
authors.lastname: Noh
authors.forename: Young-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Chang-Sun
authors.initials: CS
authors.lastname: Hwang
authors.forename: Jong-Il
authors.initials: JI
authors.lastname: Kim
authors.forename: Yoon Hwan
authors.initials: YH
authors.lastname: Chang
authors.forename: Seok-Il
authors.initials: SI
authors.lastname: Hong
authors.forename: Young-Jun
authors.initials: YJ
authors.lastname: Hong
authors.forename: In-Chul
authors.initials: IC
authors.lastname: Park
authors.forename: Jin Kyung
authors.initials: JK
authors.lastname: Lee
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D061986:MCF-7 Cells; D013629:Tamoxifen / Q000494:pharmacology* / Q000633:toxicity; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects* / Q000502:physiology; D025262:Vacuolar Proton-Translocating ATPases / Q000037:antagonists & inhibitors*
chemical_list: C497249:DDIT3 protein, human; D013629:Tamoxifen; D051742:Transcription Factor CHOP; D025262:Vacuolar Proton-Translocating ATPases
keywords: Breast cancer; CHOP; Estrogen receptor; HER2; Tamoxifen; Vacuolar H+ ATPase