Acrolein preferentially damages nucleolus eliciting ribosomal stress and apoptosis in human cancer cells
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Hsiang-tsui Wang1, Tzu-ying Chen1, Ching-wen Weng1, Chun-hsiang Yang1, Moon-shong Tang2
1Department of Pharmacology, National Yang-Ming University, Taipei, Taiwan
2Department of Environmental Medicine, Pathology and Medicine, New York University School of Medicine, Tuxedo Park, NY, USA
Hsiang-tsui Wang, email: [email protected]
Keywords: acrolein, DNA damages, rDNA/ rRNA, ribosomal stress/ nucleolar stress, RPL11-MDM2-p53
Received: July 25, 2016 Accepted: October 06, 2016 Published: October 12, 2016
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.
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