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Unlocking ferroptosis in prostate cancer — the road to novel therapies and imaging markers

Nature Reviews Urology (2024)Cite this article

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Abstract

Ferroptosis is a distinct form of regulated cell death that is predominantly driven by the build-up of intracellular iron and lipid peroxides. Ferroptosis suppression is widely accepted to contribute to the pathogenesis of several tumours including prostate cancer. Results from some studies reported that prostate cancer cells can be highly susceptible to ferroptosis inducers, providing potential for an interesting new avenue of therapeutic intervention for advanced prostate cancer. In this Perspective, we describe novel molecular underpinnings and metabolic drivers of ferroptosis, analyse the functions and mechanisms of ferroptosis in tumours, and highlight prostate cancer-specific susceptibilities to ferroptosis by connecting ferroptosis pathways to the distinctive metabolic reprogramming of prostate cancer cells. Leveraging these novel mechanistic insights could provide innovative therapeutic opportunities in which ferroptosis induction augments the efficacy of currently available prostate cancer treatment regimens, pending the elimination of major bottlenecks for the clinical translation of these treatment combinations, such as the development of clinical-grade inhibitors of the anti-ferroptotic enzymes as well as non-invasive biomarkers of ferroptosis. These biomarkers could be exploited for diagnostic imaging and treatment decision-making.

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Fig. 1: Mechanisms of ferroptosis in prostate cancer.
Fig. 2: Combination of ferroptosis inducers with standard-of-care therapies in prostate cancer.

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Acknowledgements

We are thankful to D. Chalaire, Editing Services, Research Medical Library, The UT MD Anderson Cancer Center for helping us with the editing of the manuscript. This work was supported by grants from the Department of Defense (W81XWH-19-1-0410, W81XWH-22-1-0686 and HT9425-23-1-0424 (D.E.F.)), the National Institutes of Health (R01CA184208 (D.E.F.)), an UT MD Anderson Cancer Center Quantitative Imaging Analysis Core (QIAC) Pilot Grant (D.E.F.), and a grant from the Mike Slive Foundation for Prostate Cancer Research (D.E.F.). This work was also supported by Marilyn and Frederick R. Lummis, Jr., M.D., Fellowship in Biomedical Sciences (P.H.A.C.).

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  1. Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Pham Hong Anh Cao, Abishai Dominic, Fabiola Ester Lujan, Sanjanaa Senthilkumar, Pratip K. Bhattacharya, Daniel E. Frigo & Elavarasan Subramani

  2. The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA

    Pham Hong Anh Cao & Fabiola Ester Lujan

  3. Mayo Clinic Alix School of Medicine, Rochester, MN, USA

    Sanjanaa Senthilkumar

  4. Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Daniel E. Frigo

  5. Center for Nuclear Receptors and Cell Signalling, University of Houston, Houston, TX, USA

    Daniel E. Frigo

  6. Department of Biology and Biochemistry, University of Houston, Houston, TX, USA

    Daniel E. Frigo

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D.E.F., P.H.A.C., A.D., F.E.L., S.S. and E.S. researched data for the article. D.E.F., P.H.A.C., A.D., P.K.B. and E.S. contributed substantially to discussion of the content. P.H.A.C., A.D., F.E.L., S.S. and E.S. wrote the article. D.E.F., P.H.A.C., A.D., P.K.B. and E.S. reviewed and/or edited the manuscript before submission.

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D.E.F. has received research funding from GTx, Inc., and has a familial relationship with Biocity Biopharmaceuticals, Hummingbird Bioscience, Bellicum Pharmaceuticals, Maia Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals and Barricade Therapeutics. The other authors declare no competing interests.

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Cao, P.H.A., Dominic, A., Lujan, F.E. et al. Unlocking ferroptosis in prostate cancer — the road to novel therapies and imaging markers. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-024-00869-9

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