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TRAIL-mediated signaling in prostate, bladder and renal cancer

Nature Reviews Urology volume 8, pages 417–427 (2011)Cite this article

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Abstract

Tumor necrosis factor related apoptosis inducing ligand (TRAIL) is a death receptor ligand that has the ability to preferentially initiate apoptosis in malignant cells with minimal toxicity to normal cells. TRAIL-based therapeutics, including recombinant TRAIL, TRAIL-receptor agonistic antibodies and TRAIL gene therapy, have now entered clinical trials. Although these therapeutics are promising, concerns regarding TRAIL resistance are causing research efforts to shift towards the identification of effective combination therapies. Small-molecule inhibitors, natural compounds, and drugs approved for treatment of diseases other than cancer have been shown to affect TRAIL receptors, antiapoptotic proteins and survival pathways in prostate, bladder and renal cell lines and in preclinical models. Changes in endogenous TRAIL and TRAIL receptor expression during the development of genitourinary malignancies and the way in which the expression pattern is affected by treatment are of great interest, and understanding the biological consequences of such changes will be important to maximize the potential of TRAIL-based therapeutics.

Key Points

  • Changes in the tumor necrosis factor related apoptosis inducing ligand (TRAIL) signaling pathway have been detected in genitourinary cancers but its exact contribution to cancer development, progression, and treatment responses remains unknown

  • TRAIL signaling seems to be a 'double-edged sword' that can inhibit tumor growth, but can also promote it through nonapoptotic signaling pathways

  • TRAIL signaling could potentially be used to predict outcome and treatment response in genitourinary cancers, and combination therapies targeting TRAIL could drive tumor cells into apoptosis by preventing nonapoptotic TRAIL signaling

  • Small-molecule inhibitors and natural compounds can enhance susceptibility to TRAIL via mechanisms including increased TRAIL receptor expression, decreased expression of antiapoptotic proteins or inhibition of survival pathways

  • Identification of aberrations in TRAIL apoptotic signaling in a specific type, grade, stage, or even an individual tumor will be important for maximal efficacy of combination therapy

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Figure 1: TRAIL-induced apoptosis.
Figure 2: Potential contributions of TRAIL signaling in prostate cancer.
Figure 3: Potential contribution of TRAIL signaling in renal cell carcinoma.

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Acknowledgements

The author would like to thank Dr. Steven J. Savage from the Department of Urology at MUSC for critical reading of the manuscript.

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  1. Department of Microbiology & Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, 29425, SC, USA

    Christina Voelkel-Johnson

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Voelkel-Johnson, C. TRAIL-mediated signaling in prostate, bladder and renal cancer. Nat Rev Urol 8, 417–427 (2011). https://doi.org/10.1038/nrurol.2011.81

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