title: Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells.
abstract: Acrolein (Acr) is a potent cytotoxic and DNA damaging agent which is ubiquitous in the environment and abundant in tobacco smoke. Acr is also an active cytotoxic metabolite of the anti-cancer drugs cyclophosphamide and ifosfamide. The mechanisms via which Acr exerts its anti-cancer activity and cytotoxicity are not clear. In this study, we found that Acr induces cytotoxicity and cell death in human cancer cells with different activities of p53. Acr preferentially binds nucleolar ribosomal DNA (rDNA) to form Acr-deoxyguanosine adducts, and induces oxidative damage to both rDNA and ribosomal RNA (rRNA). Acr triggers ribosomal stress responses, inhibits rRNA synthesis, reduces RNA polymerase I binding to the promoter of rRNA gene, disrupts nucleolar integrity, and impairs ribosome biogenesis and polysome formation. Acr causes an increase in MDM2 levels and phosphorylation of MDM2 in A549 and HeLa cells which are p53 active and p53 inactive, respectively. It enhances the binding of ribosomal protein RPL11 to MDM2 and reduces the binding of p53 and E2F-1 to MDM2 resulting in stabilization/activation of p53 in A549 cells and degradation of E2F-1 in A549 and HeLa cells. We propose that Acr induces ribosomal stress which leads to activation of MDM2 and RPL11-MDM2 binding, consequently, activates p53 and enhances E2F-1 degradation, and that taken together these two processes induce apoptosis and cell death.
authors.affiliation: Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsiang-Tsui
authors.initials: HT
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Tzu-Ying
authors.initials: TY
authors.lastname: Chen
authors.affiliation: Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Ching-Wen
authors.initials: CW
authors.lastname: Weng
authors.affiliation: Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chun-Hsiang
authors.initials: CH
authors.lastname: Yang
authors.affiliation: Department of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo Park, NY, USA.
authors.forename: Moon-Shong
authors.initials: MS
authors.lastname: Tang
mesh_terms: D000072283:A549 Cells; D000171:Acrolein / Q000378:metabolism / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001665:Binding Sites; D002466:Cell Nucleolus / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018736:DNA Adducts / Q000378:metabolism; D004275:DNA, Ribosomal / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000187:drug effects*; D011401:Promoter Regions, Genetic; D055550:Protein Stability; D059748:Proteolysis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics / Q000378:metabolism; D012318:RNA Polymerase I / Q000378:metabolism; D012335:RNA, Ribosomal / Q000096:biosynthesis / Q000235:genetics; D012269:Ribosomal Proteins / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D018736:DNA Adducts; D004275:DNA, Ribosomal; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; D012335:RNA, Ribosomal; D012269:Ribosomal Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C027624:ribosomal protein L11; D000171:Acrolein; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; D012318:RNA Polymerase I
keywords: DNA damages; RPL11-MDM2-p53; acrolein; rDNA/ rRNA; ribosomal stress/ nucleolar stress