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Therapeutic potential of ReACp53 targeting mutant p53 protein in CRPC

Prostate Cancer and Prostatic Diseases volume 23, pages 160–171 (2020)Cite this article

Subjects

Abstract

Backgrounds

p53 is a tumor suppressor that prevents cancer onset and progression, and mutations in the p53 gene cause loss of the tumor suppressor function of the protein. The mutant p53 protein in tumor cells can form aggregates which contribute to the dominant-negative effect over the wild-type p53 protein, causing loss of p53 tumor suppression or gain of novel oncogenic functions. Mutations in p53 have been implicated in the pathogenesis of primary prostate cancer (PCa), and are often detected in recurrent and metastatic disease. Thus, targeting mutant p53 may constitute an alternative therapeutic strategy for advanced PCa for which there are no other viable options.

Methods

In this study, we used immunoprecipitation, immunofluorescence, clonogenic survival, and cell proliferation assays, flow cytometric analysis and in vivo xenograft to investigate the biological effects of ReACp53, a cell-permeable peptide inhibitor of p53 aggregation, on mutant p53-carrying PCa cells.

Results

Our results show that ReACp53 targets amyloid aggregates of mutant p53 protein and restores the p53 nuclear function as transcriptional factor, induces mitochondrial cell death and reduces DNA synthesis of mutant p53-carrying PCa cells; ReACp53 also inhibits xenograft tumor growth in vivo.

Conclusions

The data presented here suggest a therapeutic potential of targeting mutant p53 protein in advanced PCa setting, which has a clinical impact for aggressive PCa with transforming how such tumors are managed.

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Acknowledgements

The authors thank Dr. David Eisenberg and Dr. Alice Soragni from David Geffen School of Medicine, UCLA for providing ReACp53 and its scramble control, and for their helpful comments and advice on experimental design.

Funding

This work is supported by Stand Up to Cancer–Prostate Cancer Foundation–Prostate Dream Team Translational Cancer Research Grant (SU2C-AACR-DT0812). This research grant was made possible by the generous support of the Movember Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. Jiaoti Huang is supported by grants from the National Institutes of Health (1R01CA181242, 1R01CA172603, 1R01CA205001, 1U54CA217297, 1R01CA212403, 1R01CA200853), Department of Defense Prostate Cancer Research Program (PC150382), and Prostate Cancer Foundation (Joyce and Larry Stupski Prostate Cancer Precision Oncology Special Challenge award). Lingfan Xu is supported by grants from National Natural Science Foundation (81902611), Youth Culturing Plan of National Natural Science Foundation (2018Kj16) and Anhui Natural Science Foundation (1908085QH337). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the paper.

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  1. These authors contributed equally: Yaqun Zhang, Lingfan Xu.

Authors and Affiliations

  1. Department of Urology, Beijing Hospital, National Center of Gerontology, Beijing, China

    Yaqun Zhang

  2. Department of Pathology, Duke University Medicine, Durham, NC, USA

    Lingfan Xu, Yan Chang, YanJing Li, William Butler, Er Jin, Aifen Wang, Yulei Tao, Xufeng Chen & Jiaoti Huang

  3. Department of Urology, the First Affiliated Hospital of Anhui Medical University, Hefei, China

    Lingfan Xu & Chaozhao Liang

  4. Institute of Clinical Pharmascology, Anhui Medical University, Hefei, Anhui, China

    Yan Chang

  5. Department of Respiratory Medicine, Hangzhou First People’s Hospital, Hangzhou, China

    Er Jin

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Zhang, Y., Xu, L., Chang, Y. et al. Therapeutic potential of ReACp53 targeting mutant p53 protein in CRPC. Prostate Cancer Prostatic Dis 23, 160–171 (2020). https://doi.org/10.1038/s41391-019-0172-z

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