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Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells.
Oncotarget 2016; 7(49):80450-80464O

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+Show Affiliations

Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan.Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan.Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan.Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan.Department of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo Park, NY, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27741518

Citation

Wang, Hsiang-Tsui, et al. "Acrolein Preferentially Damages Nucleolus Eliciting Ribosomal Stress and Apoptosis in Human Cancer Cells." Oncotarget, vol. 7, no. 49, 2016, pp. 80450-80464.
Wang HT, Chen TY, Weng CW, et al. Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells. Oncotarget. 2016;7(49):80450-80464.
Wang, H. T., Chen, T. Y., Weng, C. W., Yang, C. H., & Tang, M. S. (2016). Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells. Oncotarget, 7(49), pp. 80450-80464. doi:10.18632/oncotarget.12608.
Wang HT, et al. Acrolein Preferentially Damages Nucleolus Eliciting Ribosomal Stress and Apoptosis in Human Cancer Cells. Oncotarget. 2016 Dec 6;7(49):80450-80464. PubMed PMID: 27741518.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells. AU - Wang,Hsiang-Tsui, AU - Chen,Tzu-Ying, AU - Weng,Ching-Wen, AU - Yang,Chun-Hsiang, AU - Tang,Moon-Shong, PY - 2016/07/25/received PY - 2016/10/06/accepted PY - 2016/10/16/pubmed PY - 2018/2/23/medline PY - 2016/10/15/entrez KW - DNA damages KW - RPL11-MDM2-p53 KW - acrolein KW - rDNA/ rRNA KW - ribosomal stress/ nucleolar stress SP - 80450 EP - 80464 JF - Oncotarget JO - Oncotarget VL - 7 IS - 49 N2 - 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. SN - 1949-2553 UR - https://www.unboundmedicine.com/medline/citation/27741518/Acrolein_preferentially_damages_nucleolus_eliciting_ribosomal_stress_and_apoptosis_in_human_cancer_cells_ L2 - http://www.impactjournals.com/oncotarget/misc/linkedout.php?pii=12608 DB - PRIME DP - Unbound Medicine ER -