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

Abstract

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 over-

Angiotensin-(1–1) Suppresses Hepatocellular Carcinoma Growth and Angiogenesis via Complex Interactions of Angiotensin II Type 1 Receptor, Angiotensin II Type 2 Receptor and Mas Receptor

“…By contrast, signaling though AT 2 R is linked to the promotion of apoptosis. In prostate cancer cells, AT 2 R overexpression induced apoptosis independently of Ang II but depended on p38-MAPK, caspase 3 and caspase 8 and was mediated via an extrinsic cell death-signaling pathway that partially depended on P53 activation (29). Consistent with this, AT 2 R overexpression in hepatocellular carcinoma cells also induced apoptosis, which was associated with a significant increase in caspase 3 activity and p38 phosphorylation (25).…”

The renin-angiotensin system meets the hallmarks of cancer

“…In prostate cancer cells, AT2R overexpression induced apoptosis independently of AngII but was dependent on p38 mitogen-activated protein kinase (MAPK), caspase 8 and caspase 3 and was mediated through an extrinsic cell death-signalling pathway that was partially dependent on TP53, but not P21, activation. 16 Consistent with this, AT2R overexpression in a human lung adenocarcinoma cell line also reduced cellular viability and increased apoptosis, which was associated with a significant reduction in procaspase 3 levels. Thus, a disruption in the stoichiometry of the AT1R and AT2R and/or alterations of their signalling could influence whether cancer cells undergo apoptosis or survive in response to RAS activation.…”

“…Thus, a disruption in the stoichiometry of the AT1R and AT2R and/or alterations of their signalling could influence whether cancer cells undergo apoptosis or survive in response to RAS activation. 16 …”

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…Upregulated AT 2 receptor expression as seen in remodeling adult tissues and developing fetal tissue can initiate constitutive signal transduction without AngII stimulation, leading to apoptosis . Stimulation of apoptosis in prostate cancer cells was mediated by increased expression of the AT 2 receptor (Li et al, 2009b). AT 2 receptor gene transfer in the same cells mediated increased expression of bradykinin and iNOS in VSMCs.…”