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Cks overexpression enhances chemotherapeutic efficacy by overriding DNA damage checkpoints

Oncogene volume 34, pages 1961–1967 (2015)Cite this article

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Abstract

Cdc kinase subunit (Cks) proteins Cks1 and Cks2 are adaptor-like proteins that bind many cyclin-dependent kinases. A wealth of clinical data has shown that Cks proteins are overexpressed in many types of human cancers and this often correlates with increased tumor aggressiveness. Previously, we showed that Cks overexpression abrogates the intra-S-phase checkpoint, a major barrier to oncogene-mediated transformation. Interestingly, the intra-S-phase checkpoint is crucial for the cellular response to replication stress, a major pathway of apoptosis induction by many chemotherapeutic agents. Here, we demonstrate cancer cells that overexpress Cks1 or Cks2 override the intra-S-phase checkpoint in the presence of replication stress-inducing chemotherapies such as 5-Fluorouracil (5-FU) and methotrexate (MTX) leading to enhanced sensitivity in vitro and in vivo. Furthermore, enforced expression of Cks1 in an MTX-resistant breast cancer cell line was found to restore drug sensitivity. Our results suggest that Cks proteins are important determinants of apoptosis induction of replication stress-inducing chemotherapies such as 5-FU.

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Acknowledgements

We wish to thank C Torres and Y Altman (Sanford-Burnham Medical Research Institute) for technical assistance with flow cytometry analyses. This work was supported by grants from the American Cancer Society (RSG-06-020-01) and National Institutes of Health (7R01HD049539-05) to CS, Department of Defense Breast Cancer Research Program (W81XWH-06-1-0344) to SVdR, and National Cancer Institute (CA074224) to SIR. Additional support came from a UCLH/UCL Comprehensive Biomedical Research Centre grant and was undertaken at UCLH/UCL, which received a portion of its funding from the Department of Health NIHR Biomedical Research Centres funding scheme.

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Author notes

  1. S V del Rincón and M Widschwendter: These authors contributed equally to this work.

Authors and Affiliations

  1. Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA,

    S V del Rincón, D Sun, Z Ellederova, E Grolieres & C Spruck

  2. Department of Gynaecological Oncology, University College London, London, UK

    M Widschwendter

  3. Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA,

    S Ekholm-Reed, J Tat, L K Teixeira & S I Reed

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  1. S V del Rincón
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Correspondence to C Spruck.

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del Rincón, S., Widschwendter, M., Sun, D. et al. Cks overexpression enhances chemotherapeutic efficacy by overriding DNA damage checkpoints. Oncogene 34, 1961–1967 (2015). https://doi.org/10.1038/onc.2014.137

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  • DOI: https://doi.org/10.1038/onc.2014.137

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