Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: a possibility of tyrosine kinase inhibitor of growth factor.
Angiotensin II (A-II) receptor (AT(1) receptor) blockers (ARB) are a class of antihypertensive agent. It is known that they suppress signal transduction pathways mediated by growth factors [e.g., epidermal growth factor (EGF)] through the AT(1) receptor in vascular endothelial cells. In the present study, we demonstrated that A-II activates the cell proliferation of prostate cancer as well as EGF. In addition, we showed that A-II induces the phosphorylations of mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 3 (STAT3) in prostate cancer cells. In contrast, ARB was shown to inhibit the proliferation of prostate cancer cells stimulated with EGF or A-II, the mechanism of which is through the suppression of MAPK or STAT3 phosphorylation by ARB. Oral administration of ARB to nude mice inhibited the growth of prostate cancer xenografts in both androgen-dependent and androgen-independent cells in a dose-dependent manner. Microvessel density was reduced in xenografts treated with ARB, which means ARB inhibits the vascularization of xenografts. Expression of AT(1) receptor mRNA was examined by reverse transcription-PCR using 10 pairs of human prostate cancer and normal prostate tissues. AT(1) receptor expression in human prostate cancer tissue was higher (9 of 10 cases) than that in normal prostate tissue. These results suggest the possibility that ARB is a novel therapeutic class of agents for prostate cancer, especially hormone-independent tumors.
Uemura
Hiroji
H
Department of Urology, First Department of Physiology, and Second Department of Pathology, Yokohama City University Graduate School of Medicine, Yokohama, Japan. hu0428@med.Yokohama-cu.ac.jp
Ishiguro
Hitoshi
H
Nakaigawa
Noboru
N
Nagashima
Yoji
Y
Miyoshi
Yasuhide
Y
Fujinami
Kiyoshi
K
Sakaguchi
Akihiro
A
Kubota
Yoshinobu
Y
D000230:Adenocarcinoma / Q000473:pathology; D000804:Angiotensin II / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009368:Neoplasm Transplantation; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000473:pathology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011945:Receptors, Angiotensin / Q000235:genetics / Q000378:metabolism; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000187:drug effects; D015534:Trans-Activators / Q000378:metabolism; D014407:Tumor Cells, Cultured
D057911:Angiotensin Receptor Antagonists; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011945:Receptors, Angiotensin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494087:Stat3 protein, mouse; D015534:Trans-Activators; D000804:Angiotensin II; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; D020928:Mitogen-Activated Protein Kinases