Silencing of CD24 enhances the PRIMA-1-induced restoration of mutant p53 in prostate cancer cells

Purpose: In prostate cancer (PCa) 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 PCa cells. Experimental Design: Overall, 543 PCas (522 formalin-fixed paraffin-embedded and 21 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 PCa 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 PCa cells. Silencing of CD24 enhanced restoration of PRIMA-1-induced mutant p53 in endogenous TP53P223L/V274F DU145 cells and in PC3 cells transfected with TP53R273H. Conclusions: In human PCas, there is CD24-dependent inactivation of mutant p53. The co-expression of CD24 and p53 may help identify aggressive cancers. Targeting CD24 provides a strategy to enhance mutant p53-restoring therapies, especially in patients with TP53R273H PCa.

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