rAAV-Delivered PTEN Therapeutics for Prostate Cancer

Abstract

Background: Prostate cancer (PCa) is the second most popular diagnosed cancer and the fifth leading cause of cancer-related mortality for males globally. At present, effective treatments for PCa need to be further developed. To further understand the molecular mechanism and develop novel therapeutics for PCa, the role of phosphatase and tensin homolog (PTEN) signaling in PCa progression was investigated. Previous studies have reported that PTEN and its downstream target cyclin-dependent kinase inhibitor 1B (CDKN1B) are significantly downregulated in PCa cells compared to normal controls; therefore, modulation of PTEN and CDKN1B expression might be a promising therapeutic approach for PCa treatment. Methods: The expression of PTEN and CDKN1B was first verified in specimens from PCa patients or transgenic adenocarcinoma mouse prostate (TRAMP) mice. The effect of PTEN on PCa cell migration, apoptosis and cell cycle was analyzed by wound healing assay and flow cytometry in vitro. Next, we tested the concept of intraprostatic and intratumoral injection of recombinant adeno-associated virus (rAAV) 9 expressing Pten or Cdkn1b (4x1011 genome copies (GCs)/prostate) into 8-week-old TRAMP mice and a subcutaneous tumor xenograft mouse model (5x1011 GCs/tumor), respectively, to inhibit PCa progression. Results: PTEN and CDKN1B were significantly downregulated in human and mouse PCa samples, and CDKN1B expression was positively correlated with PTEN expression. Further, PTEN overexpression significantly inhibited the cell migration and cell cycle progression and promoted the apoptosis of PCa cells by decreasing Ccnd1 expression and increasing Cdkn1b expression. Importantly, rAAV9.Pten or rAAV9.Cdkn1b treatment significantly extended the lifespan of TRAMP mice and inhibited the growth rate of tumor xenografts by regulating downstream gene expression. Moreover, we confirmed that neoplasia in the treated prostates was significantly diminished compared to that in the control prostates and that apoptosis was markedly observed in xenografts treated with Pten or Cdkn1b, highlighting changes in two crucial factors for PCa progression. Conclusions: Taken together, these data indicate that rAAV-based PTEN/CDKN1B delivery holds promise for the development of novel therapeutics for PCa.