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Autophagy as a modulator and target in prostate cancer

Nature Reviews Urology volume 11, pages 508–516 (2014)Cite this article

Subjects

Key Points

  • Autophagy is a dynamic metabolic process that facilitates nutrient utilization and toxin removal: too little or too much autophagy can have beneficial or deleterious effects depending on the context

  • Understanding the context-dependent role of autophagy in cancer development, and specifically in treatment resistance, has the potential to improve current treatment of advanced prostate cancer

  • Preclinical prostate cancer models show significant upregulation of autophagy in response to androgen deprivation therapy, taxane-based chemotherapy, targeted inhibition of kinases, and amino acid restriction

  • Adjuvant autophagy inhibition in preclinical prostate cancer models improves cell killing and tumour responsiveness to treatment

  • Several autophagic modulators are under active investigation in clinical trials, including chloroquine and hydroxychloroquine

  • Currently available autophagy modulators are relatively nonspecific, and cytotoxicity in noncancerous tissues is a concern: moving forward, refinement of autophagy modulation is needed

Abstract

Autophagy, or 'self-eating', is an adaptive process that enables cells to cope with metabolic, toxic, and even infectious stressors. Although the adaptive capability of autophagy is generally considered beneficial, autophagy can also enhance nutrient utilization and improve growth characteristics of cancer cells. Moreover, autophagy can promote greater cellular robustness in the context of therapeutic intervention. In advanced prostate cancer, preclinical data provide evidence that autophagy facilitates both disease progression and therapeutic resistance. Notably, androgen deprivation therapy, taxane-based chemotherapy, targeted kinase inhibition, and nutrient restriction all induce significant cellular distress and, subsequently, autophagy. Understanding the context-dependent role of autophagy in cancer development and treatment resistance has the potential to improve current treatment of advanced prostate cancer. Indeed, preclinical studies have shown that the pharmacological inhibition of autophagy (with agents including chloroquine, hydroxychloroquine, metformin, and desmethylclomipramine) can enhance the cell-killing effect of cancer therapeutics, and a number of these agents are currently under investigation in clinical trials. However, many of these autophagy modulators are relatively nonspecific, and cytotoxicity in noncancerous tissues is still a concern. Moving forward, refinement of autophagy modulation is needed.

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Figure 1: Initiation and mechanisms of autophagy.
Figure 2: Prostate cancer treatments and autophagy.
Figure 3: Src kinase, autophagy and prostate cancer.
Figure 4: Amino acid deprivation, autophagy and prostate cancer.

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Acknowledgements

The work is supported by funding from the following sources: the Department of Defense, the Stand Up To Cancer Prostate Cancer Foundation Prostate Dream Team Translational Cancer Research grant, made possible by the generous support of the Movember Foundation (Stand Up To Cancer is a programme of the Entertainment Industry Foundation administered by the American Association of Cancer Research), and the National Center for Advancing Translational Sciences at the National Institutes of Health, through grant number UL1 TR000002 and the linked TL1 TR000133 award.

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  1. Department of Urology, School of Medicine, University of California, Davis, 4860 Y Street, Sacramento, 95817, CA, USA

    Jason M. Farrow, Joy C. Yang & Christopher P. Evans

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All authors researched data for the article, and contributed to discussions of content, and review and editing of the manuscript before submission. J.M.F. wrote the article.

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Correspondence to Christopher P. Evans.

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Farrow, J., Yang, J. & Evans, C. Autophagy as a modulator and target in prostate cancer. Nat Rev Urol 11, 508–516 (2014). https://doi.org/10.1038/nrurol.2014.196

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