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Defining a role for sphingosine kinase 1 in p53-dependent tumors

Oncogene volume 31, pages 1166–1175 (2012)Cite this article

Abstract

p53 is a crucial tumor suppressor that is mutated or deleted in a majority of cancers. Exactly how p53 prevents tumor progression has proved elusive for many years; however, this information is crucial to define targets for chemotherapeutic development that can effectively restore p53 function. Bioactive sphingolipids have recently emerged as important regulators of proliferative, apoptotic and senescent cellular processes. In this study, we demonstrate that the enzyme sphingosine kinase 1 (SK1), a critical enzyme in the regulation of the key bioactive sphingolipids ceramide, sphingosine and sphingosine-1-phosphate (S1P), serves as a key downstream target for p53 action. Our results show that SK1 is proteolysed in response to genotoxic stress in a p53-dependent manner. p53 null mice display elevation of SK1 levels and a tumor-promoting dysregulation of bioactive sphingolipids in which the anti-growth sphingolipid ceramide is decreased and the pro-growth sphingolipid S1P is increased. Importantly, deletion of SK1 in p53 null mice completely abrogated thymic lymphomas in these mice and prolonged their life span by ∼30%. Deletion of SK1 also significantly attenuated the formation of other cancers in p53 heterozygote mice. The mechanism of p53 tumor suppression by loss of SK1 is mediated by elevations of sphingosine and ceramide, which in turn were accompanied by increased expression of cell cycle inhibitors and tumor cell senescence. Thus, targeting SK1 may restore sphingolipid homeostasis in p53-dependent tumors and provide insights into novel therapeutic approaches to cancer.

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Acknowledgements

This work was supported, in part, by Award Number I01BX000156 from the Biomedical Laboratory Research and Development Service of the VA Office of Research and Development, NIH/NIGMS R01 GM062887, NIH/NCI P01 CA097132—project 3 (to LMO). NIH/NCI P01 CA097132—project 1 (to YAH). American Heart Association Pre-Doctoral Fellowship AHA 081509E (to RWJ), NIH MSTP Training Grant GM08716 (to RWJ, AMDC, LAHS), MUSC Hollings Cancer Center Abney Foundation Scholarship (to RWJ, LAHS), NIH/NIEHS TG T32 ES012878, and NIH/NIEHS National Research Service Award Individual Predoctoral Fellowship F30ES017379 (to LAHS). Liquid chromatography-mass spectrometry analysis of sphingolipids was performed by Lipidomics Shared Resource, MUSC (Methods 2006, 39: 82–91) supported by NCI Grants: IPO1CA097132 and P30 CA 138313 and NIH/NCRR SC COBRE Grant P20 RR017677 as specified in Supplementary Information. Laboratory space in the CRI building of MUSC was supported by the NIH, Grant C06 RR018823 from the Extramural Research Facilities Program of the National Center for Research Resources. Refer to Supplementary Information for individual acknowledgements and the VA disclaimer.

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Authors and Affiliations

  1. Department of Molecular and Cellular Biology and Pathobiology, Medical University of South Carolina, Charleston, SC, USA

    L A Heffernan-Stroud & L M Obeid

  2. Department of Comparative Medicine/Lab Animal Resources, Medical University of South Carolina, Charleston, SC, USA

    K L Helke

  3. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA

    R W Jenkins, Y A Hannun & L M Obeid

  4. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA

    A-M De Costa

  5. Ralph H Johnson Veterans Affairs Medical Center, Charleston, SC, USA

    L M Obeid

  6. Department of Medicine, Medical University of South Carolina, Charleston, SC, USA

    L M Obeid

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Heffernan-Stroud, L., Helke, K., Jenkins, R. et al. Defining a role for sphingosine kinase 1 in p53-dependent tumors. Oncogene 31, 1166–1175 (2012). https://doi.org/10.1038/onc.2011.302

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