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p53 disruption profoundly alters the response of human glioblastoma cells to DNA topoisomerase I inhibition

Oncogene volume 23, pages 1283–1290 (2004)Cite this article

Abstract

A critical challenge in cancer research is to identify genetic lesions that sensitize patients to chemotherapy. p53, which is mutated in nearly one-third to half of glioblastomas, may be such a lesion. In this paper, we demonstrate that p53 disruption dramatically sensitizes glioblastoma cells to DNA topoisomerase I inhibitor-mediated apoptosis. Using 19 glioblastoma cell lines, including 15 low-passage ex vivo cell lines derived from patients, as well as isogenic glioblastoma cells varying in p53 status, we show that clinically relevant levels of SN-38 potently induce cell cycle arrest and temporary senescence in glioblastoma cells with wild-type p53 while causing massive apoptosis in p53-deficient cells (P<0.0002). We demonstrate that glioblastoma cells with wild-type p53 proliferate when recultured in drug-free medium, whereas p53-deficient cells do not. We also show that p16 protein expression is neither necessary nor sufficient for initiation and/or maintenance of SN-38-induced arrest/senescence. These results indicate that p53 disruption has a dramatic effect on how glioblastoma cells process topoisomerase I inhibitor-mediated DNA damage.

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Acknowledgements

We are grateful to Drs William McBride, Adrienne Scheck, Stanley Nelson, Harvey Herschman and Jonathan Braun for their helpful comments on this manuscript. We thank Dr C Patrick Reynolds for providing packaging cell lines PA317-pLXSN and PA317-pLXSN16E6. This work was supported by K08NS43147-01 from the National Institute of Neurological Disorders and Stroke (PSM) and U01 CA88127 from the National Cancer Institute (PSM is a co-PI). This work was also supported by an Accelerate Brain Cancer Cure Award, a Henry E Singleton Brain Tumor Fellowship, a generous donation from the Kevin Riley family to UCLA Comprehensive Brain Tumor Program, and the Harry Allgauer Foundation through The Doris R Ullmann Fund for Brain Tumor Research Technologies. Yinglin Wang is a postdoctoral trainee supported by Institutional National Research Service Award T32-NS07449, a Translational Research Grant from American Brain Tumor Association, and a fellowship from UCLA Jonsson Cancer Center Foundation.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, UCLA School of Medicine, 13-317 Center for the Health Science, Los Angeles, 90095-1732, CA, USA

    Yinglin Wang, Shaojun Zhu & Paul S Mischel

  2. The Henry E Singleton Brain Cancer Research Program, UCLA School of Medicine, Los Angeles, 90095, CA, USA

    Timothy F Cloughesy, Linda M Liau & Paul S Mischel

  3. Department of Neurology, UCLA School of Medicine, Los Angeles, 90095, CA, USA

    Timothy F Cloughesy

  4. Department of Neurosurgery, UCLA School of Medicine, Los Angeles, 90095, CA, USA

    Linda M Liau

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  1. Yinglin Wang
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Correspondence to Paul S Mischel.

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Wang, Y., Zhu, S., Cloughesy, T. et al. p53 disruption profoundly alters the response of human glioblastoma cells to DNA topoisomerase I inhibition. Oncogene 23, 1283–1290 (2004). https://doi.org/10.1038/sj.onc.1207244

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