Angiotensin type 2 receptor–mediated apoptosis of human prostate cancer cells

• Published in: Molecular cancer therapeutics Vol. 8; no. 12; pp. 3255 - 3265
• Main Authors: Li, Hongwei, Qi, Yanfei, Li, Chengyao, Braseth, Leah N, Gao, Yongxin, Shabashvili, Arseniy E, Katovich, Michael J, Sumners, Colin
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research 01.12.2009
• Subjects: adenoviral vector; Angiotensin II - pharmacology; angiotensin type 2 receptor; apoptosis; Apoptosis - drug effects; Apoptosis - genetics; Apoptosis - physiology; Blotting, Western; Caspase 3 - metabolism; Caspase 8 - metabolism; caspase-3; Cell Cycle - drug effects; Cell Line; Cell Line, Tumor; Cell Proliferation - drug effects; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; gene therapy; Green Fluorescent Proteins - genetics; Green Fluorescent Proteins - metabolism; Humans; In Situ Nick-End Labeling; Male; Microscopy, Fluorescence; p38 MAP kinase; p38 Mitogen-Activated Protein Kinases - genetics; p38 Mitogen-Activated Protein Kinases - metabolism; prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Receptor, Angiotensin, Type 2 - genetics; Receptor, Angiotensin, Type 2 - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Signal Transduction - drug effects; Signal Transduction - genetics; Signal Transduction - physiology; Transfection; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-09-0237

Angiotensin II (Ang II) type 1 receptor blocking drugs have been shown to inhibit the growth of prostate cancer cells and delay the development of prostate cancer. Functional Ang II type 2 receptors (AT2R) are present in these cells and inhibit growth induced by epidermal growth factor. The present studies report apoptosis of prostate cancer cells induced by AT2R overexpression. A recombinant adenoviral vector expressing AT2R (Ad-G-AT2R-EGFP) was transduced into prostate cancer cells, including androgen-independent (DU145 and PC3) and androgen-dependent cell lines (LNCaP). Following AT2R transduction, apoptosis was analyzed by terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling staining and caspase-3 activity assays. The results indicate that increased expression of AT2R alone induced apoptosis in the prostate cancer lines, an effect that did not require Ang II. AT2R overexpression in DU145 cells induced inhibition of proliferation, a significant reduction of S-phase cells, and an enrichment of G 1 -phase cells. The data also indicate that overexpression of AT2R led to apoptosis via an extrinsic cell death signaling pathway that is dependent on activation of p38 mitogen-activated protein kinase, caspase-8, and caspase-3. Finally, the apoptosis induced by AT2R overexpression is partially dependent on the activation of p53, but not on p21. The observations presented here suggest that the ability of increased AT2R expression to induce apoptosis in prostate cancer cells may have potential therapeutic implications for this disease, and suggest that AT2R is a promising novel target gene for prostate cancer gene therapy. [Mol Cancer Ther 2009;8(12):3255–65]