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Effect of an hdm-2 antagonist peptide inhibitor on cell cycle progression in p53-deficient H1299 human lung carcinoma cells

Oncogene volume 25, pages 6672–6677 (2006)Cite this article

Abstract

The hdm-2 oncogene is overexpressed in several types of malignancies including osteosarcomas, soft tissue sarcomas and gliomas and hdm-2 has been associated with accelerated tumor formation in both hereditary and sporadic cancers. Among the other key binding partners, hdm-2 forms a complex with the tumor suppressor p53, resulting in a rapid proteasome-mediated degradation of the p53 protein. This positions the hdm-2–p53 complex as an attractive target for the development of anticancer therapy and recently the first small molecule hdm-2 antagonist has been reported. Development of hdm-2 antagonists is currently focused on malignancies containing a wild-type p53 genotype, which is the case in approximately half of human cancer indications. However, hdm-2 has also been implicated in oncogenesis in the absence of p53. We therefore studied the effect of hdm-2 antagonists in p53-deficient human H1299 lung carcinoma cells. The hdm-2 antagonistic peptide caused G1 cell cycle arrest, inhibited colony growth and induced expression of G1 checkpoint regulatory proteins, such as p21waf1,cip1. These data demonstrate that hdm-2 regulates the G1 cell cycle checkpoint in a p53-independent manner, suggesting that hdm-2 antagonists represent a novel class of anticancer therapeutics with broad applicability towards tumors with different p53 genetic backgrounds.

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Acknowledgements

We thank Lut Janssen and Kristin Mertens for technical assistance and support. Special acknowledgements to Najoua Dendouga for helpful discussions about this manuscript and associated work.

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  1. Oncology Discovery Research and Early Development, Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium

    A VanderBorght, A Valckx, J Van Dun, T Grand-Perret, S De Schepper, J Vialard, M Janicot & J Arts

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  1. A VanderBorght
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  2. A Valckx
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  3. J Van Dun
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  4. T Grand-Perret
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  5. S De Schepper
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  8. J Arts
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Correspondence to J Arts.

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VanderBorght, A., Valckx, A., Van Dun, J. et al. Effect of an hdm-2 antagonist peptide inhibitor on cell cycle progression in p53-deficient H1299 human lung carcinoma cells. Oncogene 25, 6672–6677 (2006). https://doi.org/10.1038/sj.onc.1209667

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