Therapeutic potential of ReACp53 targeting mutant p53 protein in CRPC.

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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Published Version (Please cite this version)

10.1038/s41391-019-0172-z

Publication Info

Zhang, Yaqun, Lingfan Xu, Yan Chang, YanJing Li, William Butler, Er Jin, Aifen Wang, Yulei Tao, et al. (2020). Therapeutic potential of ReACp53 targeting mutant p53 protein in CRPC. Prostate cancer and prostatic diseases, 23(1). pp. 160–171. 10.1038/s41391-019-0172-z Retrieved from https://hdl.handle.net/10161/20502.

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Scholars@Duke

Butler

William Butler

Lab Research Analyst II

I received my Ph.D. in Pathology in May 2023, where my dissertation work focused on the discovery of novel biomarkers and therapeutic targets for advanced, therapy-resistant prostate cancer. In addition to my doctoral training, I hold a M.Sc. degree in Organic Chemistry and a graduate certificate in college teaching. 

As of June 2023, I will be transitioning from Duke to begin my role as a clinical chemistry fellow at Penn Medicine- University of Pennsylvania and Children's Hospital of Philadelphia. 

Huang

Jiaoti Huang

The Johnston-West Endowed Department Chair of Pathology

I am a physician-scientist with clinical expertise in the pathologic diagnosis of genitourinary tumors including tumors of the prostate, bladder, kidney and testis. Another area of interest is gynecologic tumors. In my research laboratory we study prostate cancer, focusing on molecular mechanisms of carcinogenesis and tumor progression, as well as biomarkers, imaging and novel therapeutic strategies. In addition to patient care and research, I am also passionate about education. I have trained numerous residents, fellows, graduate students and postdocs.


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