Inhibition of hypoxia-inducible factor-1α (HIF-1α) protein synthesis by DNA damage inducing agents

Lou, J. J. W., Chua, Y. L., Chew, E. H., Gao, J., Bushell, M. and Hagen, T. (2010) Inhibition of hypoxia-inducible factor-1α (HIF-1α) protein synthesis by DNA damage inducing agents. PLoS ONE, 5(5), e10522. (doi: 10.1371/journal.pone.0010522) (PMID:20479887) (PMCID:PMC2866540)

Abstract

Hypoxia-inducible factor (HIF) is a heterodimeric transcription factor that is composed of a hypoxia-inducible α subunit (HIF-1α and HIF-2α) and a constitutively expressed β subunit (HIF-1β). HIF mediates the adaptation of cells and tissues to low oxygen concentrations. It also plays an important role in tumorigenesis and constitutes an important therapeutic target in anti-tumor therapy. We have screened a number of reported HIF inhibitors for their effects on HIF-transcriptional activity and found that the DNA damage inducing agents camptothecin and mitomycin C produced the most robust effects. Camptothecin is a reported inhibitor of HIF-1α translation, while mitomycin C has been reported to induce p53-dependent HIF-1α degradation. In this study we demonstrate that the inhibitory effect of mitomycin C on HIF-1α protein expression is not dependent on p53 and protein degradation, but also involves HIF-1α translational regulation. Initiation of a DNA damage response with the small molecule p53 activator NSC-652287 (RITA) has been reported to inhibit HIF-1α protein synthesis by increasing the phosphorylation of eIF2α. However, we show here that even when eIF2α phosphorylation is prevented, the DNA damage inducing drugs mitomycin C, camptothecin and NSC-652287 still inhibit HIF-1α protein synthesis to the same extent. The inhibitory effects of camptothecin on HIF-1α expression but not that of mitomycin C and NSC-652287 were dependent on cyclin-dependent kinase activity. In conclusion, specific types of DNA damage can bring about selective inhibition of HIF-1α protein synthesis. Further characterization of the involved mechanisms may reveal important novel therapeutic targets.

• Item Type: Articles
• Additional Information: The work was supported through Cross-Faculty Research Grant funding from the Office of the Deputy President (Research & Technology) of the National University of Singapore and funding from the University of Nottingham Biomedical Research Committee.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bushell, Professor Martin
• Authors: Lou, J. J. W., Chua, Y. L., Chew, E. H., Gao, J., Bushell, M., and Hagen, T.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: PLoS ONE
• Publisher: Public Library of Science
• ISSN: 1932-6203
• ISSN (Online): 1932-6203
• Copyright Holders: Copyright © 2010 Lou et al.
• First Published: First published in PloS ONE 5(5):e10522
• Publisher Policy: Reproduced under a Creative Commons license