Silencing of CD24 Enhances the PRIMA-1–Induced Restoration of Mutant p53 in Prostate Cancer Cells
Wei Zhang1,2, Bin Yi1,3, Chao Wang1,4, Dongquan Chen5,6, Sejong Bae5,6, Shi Wei7, Rong-Jun Guo7, Changming Lu1, Lisa L.H. Nguyen1, Wei-Hsiung Yang8, James W. Lillard9, Xingyi Zhang10,*,Lizhong Wang1,6,*, and Runhua Liu1,6,*
Author Affiliations1 Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama.
2 Institute for the Endemic Fluorosis Control, Chinese Center for Endemic Disease Control, Harbin Medical University, Harbin, P.R. China.
3 Department of Pediatric Surgery, Tongji Hospital of Huazhong University of Science and Technology, Wuhan, P.R. China.
4 Department of Integrative Endemic Area, Tongji Hospital of Huazhong University of Science and Technology, Wuhan, P.R. China.
5 Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
6 Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama.
7 Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama.
8 Department of Biomedical Sciences, Mercer University, Savannah, Georgia.
9 Department of Microbiology, Biochemistry, and Immunology, Morehouse School of Medicine, Atlanta, Georgia.
10 Provincial Key Laboratory on Molecular and Chemical Genetic, The Second Hospital of Jilin University, Changchun, P.R. China.
Runhua Liu, University of Alabama at Birmingham, 720 20th Street South, Kaul 705, Birmingham, AL 35294. Phone: 205-934-7308; Fax: 205-975-5689; E-mail: email@example.com; Lizhong Wang, E-mail:firstname.lastname@example.org; Xingyi Zhang, email@example.com
W. Zhang and B. Yi contributed equally to this article.
Purpose: In prostate cancer cells, there is CD24-dependent inactivation of mutant p53, but the mechanism and its significance remain largely unknown. Here, we validated this observation and explored the therapeutic potential of targeting CD24 in TP53 mutant prostate cancer cells.
Experimental Design: Overall, 553 prostate cancers (522 formalin-fixed paraffin-embedded and 31 frozen tissues) were assessed for protein or mRNA expression of CD24 and TP53. The effects of CD24 on p53-dependent transcriptional regulation, cancer cell growth, the cell cycle, apoptosis, and mutant p53 restoration were also determined.
Results: As determined with three sample cohorts, CD24 and p53 were not expressed in prostate epithelial cells but in prostate cancer cells in 48% of cases for CD24 and 16% of cases for p53 (mutant form). Expressions of CD24 and mutant p53 were more frequently observed in late-stage and metastatic prostate tumors. Mutant p53 accompanied with CD24 was expressed in most cases (91.6%, 76/83). Silencing of CD24 increased the transcriptional activity of p53 target genes, such as CDKNA1, VDR, and TP53INP1, leading to suppression of p53-dependent cell growth, cell-cycle arrest, and apoptosis in most TP53-mutant prostate cancer cells. Silencing of CD24enhanced restoration of PRIMA-1–induced mutant p53 in endogenous TP53P223L/V274F DU145 cells and in PC3 cells transfected with TP53R273H.
Conclusions: In human prostate cancers, there is CD24-dependent inactivation of mutant p53. The coexpression of CD24 and p53 may help identify aggressive cancers. Targeting CD24provides a strategy to enhance mutant p53-restoring therapies, especially in patients withTP53R273H prostate cancer. Clin Cancer Res; 22(10); 2545–54. ©2015 AACR.
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