Histone Deacetylase Inhibitors Restore Cell Surface Expression of the Coxsackie Adenovirus Receptor and Enhance CMV Promoter Activity in Castration-Resistant Prostate Cancer Cells. (12th January 2012)

• Record Type: Journal Article
• Authors: Kasman Kasman, Laura Laura; Onicescu Onicescu, Georgiana Georgiana; Voelkel-Johnson Voelkel-Johnson, Christina Christina
• Other Names: Shinohara Shinohara Katsuto Katsuto Academic Editor.
• Is Part Of: Prostate cancer. Volume 2012(2012)
• Publication Date: 2012-01-12
• Subjects: Prostate -- Cancer -- Periodicals; Prostate -- Cancer -- Surgery -- Periodicals; 616.99463
• DOI: 10.1155/2012/137163
• Languages: English
• ISSNs: 2090-3111

Abstract

Abstract : Adenoviral gene therapy using the death receptor ligand TRAIL as the therapeutic transgene can be safely administered via intraprostatic injection but has not been evaluated for efficacy in patients. Here we investigated the efficacy of adenoviral TRAIL gene therapy in a model of castration resistant prostate cancer and found that intratumoral injections can significantly delay tumor growth but cannot eliminate established lesions. We hypothesized that an underlying cause is inefficient adenoviral delivery. Using the LNCaP progression model of prostate cancer we show that surface CAR expression decreases with increasing tumorigenicity and that castration resistant C4-2b cells were more difficult to transduce with adenovirus than castration sensitive LNCaP cells. Many genes, including CAR, are epigenetically silenced during transformation but a new class of chemotherapeutic agents, known as histone deacetylase inhibitors (HDACi), can reverse this process. We demonstrate that HDACi restore CAR expression and infectivity in C4-2b cells and enhance caspase activation in response to infection with a TRAIL adenovirus. We also show that in cells with high surface CAR expression, HDACi further enhance transgene expression from the CMV promoter. Thus HDACi have multiple beneficial effects, which may enhance not only viral but also non-viral gene therapy of castration resistant prostate cancer.