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Therapeutic potential of targeting sphingosine kinase 1 in prostate cancer

Nature Reviews Urology volume 8, pages 569–578 (2011)Cite this article

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Abstract

Sphingosine kinase 1 (SK1) is a lipid enzyme with oncogenic properties that converts the proapoptotic lipid sphingosine into the antiapoptotic lipid sphingosine-1-phosphate, which activates the signal transduction pathways that lead to cell proliferation, migration, activation of the inflammatory response and impairment of apoptosis. Compelling evidence suggests that SK1 activation contributes to cancer progression leading to increased oncogenic transformation, tumor growth, resistance to therapies, tumor neovascularization and metastatic spread. High levels of SK1 expression or activity have been associated with poor prognosis in several cancers, including those of the prostate. Recent studies using prostate cancer cell and mouse models demonstrate a significant potential for SK1-targeting therapies to synergize with the effects of docetaxel chemotherapy and radiotherapy. However, until recently the absence of clinically applicable SK1 inhibitors has limited the translation of these findings into patients. With the recent discovery that clinically approved drug fingolimod has SK1-inhibiting properties, SK1 has gained significant attention from both clinicians and the pharmaceutical industry and it is hoped that trials of newly developed SK1 inhibitors might follow soon.

Key Points

  • Sphingosine kinase 1 (SK1) is a lipid enzyme that plays a critical role in oncogenic transformation, tumor growth, resistance to therapies, tumor neovascularization and metastatic spread

  • High levels of SK1 expression and activity have been associated with prostate cancer progression (PSA, tumor volumes and Gleason score) and disease recurrence (positive margins and surgical failure)

  • In prostate cancer SK1 has been suggested to be a 'sensor' to anticancer therapies—positive outcome is associated with SK1 inhibition

  • Preclinical studies demonstrate significant potential for SK1-targeting therapies to synergize with the effects of docetaxel chemotherapy and radiotherapy

  • The first clinically applicable drug that was demonstrated to have SK1-inhibiting properties (fingolimod), was shown to induce prostate cancer radiosensitization, reducing primary tumor size and inhibiting metastasis

  • The development of a new generation of clinically applicable pharmacological SK1 inhibitors is urgently required for further preclinical and clinical studies of SK1 targeting therapies as sensitizers to prostate cancer treatment

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Figure 1: The sphingolipid biostat.
Figure 2: SK1–S1P signaling.

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  1. Division of Cancer, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, 807 Cyclotron Building, Hammersmith Hospital, Du Cane road, London, W12 0NN, UK

    Dmitri Pchejetski, Justin Stebbing & Jonathan Waxman

  2. Research and Development, Gambro, Ermelesstrasse 76, Hechingen, 72379, Germany

    Torsten Böhler

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D. Pchejetski, T. Böhler, J. Stebbing and J. Waxman contributed to researching, discussion of content and writing the article. D. Pchejetski, T. Böhler and J. Waxman reviewed the article before submission.

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Pchejetski, D., Böhler, T., Stebbing, J. et al. Therapeutic potential of targeting sphingosine kinase 1 in prostate cancer. Nat Rev Urol 8, 569–578 (2011). https://doi.org/10.1038/nrurol.2011.117

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