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A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress

Nature Medicine volume 23, pages 461–471 (2017)Cite this article

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Abstract

Cisplatin and its platinum analogs, carboplatin and oxaliplatin, are some of the most widely used cancer chemotherapeutics. Although cisplatin and carboplatin are used primarily in germ cell, breast and lung malignancies, oxaliplatin is instead used almost exclusively to treat colorectal and other gastrointestinal cancers. Here we utilize a unique, multi-platform genetic approach to study the mechanism of action of these clinically established platinum anti-cancer agents, as well as more recently developed cisplatin analogs. We show that oxaliplatin, unlike cisplatin and carboplatin, does not kill cells through the DNA-damage response. Rather, oxaliplatin kills cells by inducing ribosome biogenesis stress. This difference in drug mechanism explains the distinct clinical implementation of oxaliplatin relative to cisplatin, and it might enable mechanistically informed selection of distinct platinum drugs for distinct malignancies. These data highlight the functional diversity of core components of front-line cancer therapy and the potential benefits of applying a mechanism-based rationale to the use of our current arsenal of anti-cancer drugs.

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Figure 1: RNAi signatures identify a spectrum of platinum-drug activities.
Figure 2: Sensitivity profiles of the indicated platinum drugs on a panel of the repair-deficient DT40 mutants.
Figure 3: Phenanthriplatin and oxaliplatin exhibit distinct differences from cisplatin in cell-cycle profiles, γ-H2AX and p53 signaling in Eμ-Myc Cdkn2aArf−/− cells.
Figure 4: Immunofluorescence of γ-H2AX and comet assays reveal lack of DNA damage resulting from oxaliplatin and phenanthriplatin treatment in Eμ-Myc Cdkn2aArf−/−cells.
Figure 5: Oxaliplatin and phenanthriplatin induce ribosome biogenesis stress.
Figure 6: Evidence for sensitization to oxaliplatin in 'translation-addicted' cell lines and primary tumors.

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Acknowledgements

This work was supported by the Koch Institute Frontier Research Program through the Michael (1957) and Inara Erdei Fund and the Kathy and Curt Marble Cancer Research Fund, by the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute, by National Cancer Institute Grant CA034992 (S.J.L.), by the Integrative Cancer Biology Program grant #U54-CA112967-09 and by the Center of Cancer Research, the Intramural Program of the National Cancer Institute, NIH (Z01 BC006150-19). M.T.H. is the Chang and Eisen Associate Professor of Biology, C.E.K. was supported by award Number T32GM007753 from the National Institute of General Medical Sciences and G.Y.P. was supported by a Misrock Postdoctoral Fellowship. The authors would also like to thank the Koch Institute Swanson Biotechnology Center for technical support, specifically G. Paradis of the Flow Cytometry Core Facility. We thank J. Wilson for providing platinum compounds ([Pt(tfbz)(NH3)2](NO3)) and [Pt(acac)(NH3)2](SO4)0.5) and D. Bartel for advice and discussion regarding translation and ribosome translation experiments. The authors also thank G. Walker, A. Koehler, E. Bent, C. Braun, E. Kreidl and B. Zhao for comments and discussion on the paper and N. Fenouille, H. Criscione and F. Lam for technical assistance. The authors thank S. Takeda and M. Takata (Kyoto University, Japan) for providing us with the mutant DT40 cell lines used in this study. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of General Medical Sciences or the National Institutes of Health.

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Authors and Affiliations

  1. The Koch Institute for Integrative Cancer Research at MIT, Cambridge, Massachusetts, USA

    Peter M Bruno, Yunpeng Liu, Catherine E Koch, Justin R Pritchard, Stephen J Lippard & Michael T Hemann

  2. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Peter M Bruno, Yunpeng Liu, Catherine E Koch, Timothy J Eisen, Justin R Pritchard & Michael T Hemann

  3. Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

    Ga Young Park & Stephen J Lippard

  4. Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Institutes of Health, Bethesda, Maryland, USA

    Junko Murai & Yves Pommier

  5. Howard Hughes Medical Institute, Whitehead Institute for Biomedical Research, Cambridge, Massachusetts, USA

    Timothy J Eisen

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Contributions

P.M.B., Y.L., G.Y.P., T.J.E., J.R.P., Y.P., S.J.L. and M.T.H. conceived the idea for the research, designed experiments and interpreted data. P.M.B., Y.L. and C.E.K. performed experiments. P.M.B. and Y.L. performed bioinformatic analyses. J.M. performed DT40 sensitivity profiles. T.J.E. performed polysome gradient profiling. P.M.B., S.J.L. and M.T.H. wrote the paper.

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Correspondence to Stephen J Lippard or Michael T Hemann.

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Bruno, P., Liu, Y., Park, G. et al. A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress. Nat Med 23, 461–471 (2017). https://doi.org/10.1038/nm.4291

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