title: Doxorubicin prevents endoplasmic reticulum stress-induced apoptosis.
abstract: Several cellular stress signaling pathways initiate apoptosis in eukaryotic cells, but the interactions and coordination between the pathways have not been elucidated. In this study, apoptosis was triggered in MCF7 human breast carcinoma cells using doxorubicin, a topoisomerase inhibitor, and an endoplasmic reticulum (ER) stress inducer, thapsigargin, the latter causing the unfolded protein response (UPR). Interestingly, compared to treatment with doxorubicin or thapsigargin alone, cell death was reduced by treatment with both stress inducers. In contrast to another topoisomerase inhibitor, etoposide, doxorubicin markedly decreased apoptosis induced by thapsigargin; this doxorubicin effect was accompanied by reduced expression of the UPR-specific proapoptotic protein, C/EBP-homologous protein, and its upstream transcription factor, ATF4. We further found that doxorubicin downregulates the expression of ATF4 mRNA, indicating that doxorubicin interferes with the UPR at the level of ATF4 transcription. Taken together, the data suggest that ER stress-initiated cell death might be regulated by doxorubicin.
authors.affiliation: Laboratory of Human Genomics, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea. crystal@kribb.re.kr
authors.forename: Soo Jung
authors.initials: SJ
authors.lastname: Kim
authors.forename: Kyung Mi
authors.initials: KM
authors.lastname: Park
authors.forename: Nayoung
authors.initials: N
authors.lastname: Kim
authors.forename: Young Il
authors.initials: YI
authors.lastname: Yeom
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D006801:Humans; D017510:Protein Folding; D012333:RNA, Messenger / Q000235:genetics; D019284:Thapsigargin / Q000494:pharmacology
chemical_list: C497109:ATF4 protein, human; D012333:RNA, Messenger; D051701:Activating Transcription Factor 4; D019284:Thapsigargin; D004317:Doxorubicin