The combination of the prodrugs perforin-CEBPD and perforin-granzyme B efficiently enhances the activation of caspase signaling and kills prostate cancer

• Published in: Cell death & disease Vol. 5; no. 5; p. e1220
• Main Authors: Chuang, C-H, Wang, W-J, Li, C-F, Ko, C-Y, Chou, Y-H, Chuu, C-P, Cheng, T-L, Wang, J-M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.05.2014; Springer Nature B.V; Nature Publishing Group
• Subjects: 631/80/82/23; 692/699/67/589/466; 692/700/565/1436/1437; Animals; Antibodies; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Apoptosis - drug effects; BALB 3T3 Cells; Binding Sites; Biochemistry; Biomedical and Life Sciences; Caspase 3 - metabolism; Caspase 8 - genetics; Caspase 8 - metabolism; CCAAT-Enhancer-Binding Protein-delta - pharmacology; Cell Biology; Cell Culture; Cell Line, Tumor; Cell Proliferation - drug effects; E2F1 Transcription Factor - genetics; E2F1 Transcription Factor - metabolism; Enhancer of Zeste Homolog 2 Protein; Enzyme Activation; Gene Expression Regulation, Neoplastic; Genes, Reporter; Granzymes - pharmacology; Humans; Immunology; Life Sciences; Male; Mice; Original; original-article; Perforin - pharmacology; Polycomb Repressive Complex 2 - genetics; Polycomb Repressive Complex 2 - metabolism; Prodrugs - metabolism; Prodrugs - pharmacology; Promoter Regions, Genetic; Prostatic Neoplasms - enzymology; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Receptors, Androgen - drug effects; Receptors, Androgen - metabolism; Recombinant Fusion Proteins - pharmacology; Signal Transduction - drug effects; Time Factors; Transfection; prodrug; prostate cancer; androgen; CEBPD; epigenetic regulation
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/cddis.2014.106

The survival of prostate cancer (PrCa) patients is associated with the transition to hormone-independent tumor growth and metastasis. Clinically, the dysregulation of androgen action has been associated with the formation of PrCa and the outcome of androgen deprivation therapy in PrCa. CCAAT/enhancer binding protein delta (CEBPD) is a transcription factor that has been reported to act as an oncogene or tumor suppressor, depending on the extra- and intracellular environments following tumorigenesis. We found that androgen can activate CEBPD transcription by direct binding of the androgen receptor (AR) to the CEBPD promoter region. Increases of suppressor of zeste 12 (SUZ12) and enhancer of zeste homolog 2 (EZH2) attenuated the androgen-induced transcription of CEBPD . Importantly, the increases in E2F1, SUZ12 and EZH2 as well as the inactivation of CEBPD were associated with the clinicopathological variables and survival of PrCa patients. We revealed that caspase 8 (CASP8), an apoptotic initiator, is responsive to CEBPD induction. Reporter and in vivo DNA-binding assays revealed that CEBPD directly binds to and activates CASP8 reporter activity. A prodrug system was developed for therapeutic application in AR-independent or androgen-insensitive PrCa to avoid the epigenetic effects on the suppression of CEBPD expression. Our results showed that the combination of a perforin (PF)-CEBPD prodrug (which increases the level of procaspase-8) and a PF-granzyme B prodrug (which activates CASP8 and caspase 3 (CASP3)) showed an additive effect in triggering the apoptotic pathway and enhancing apoptosis in PrCa cells.