Angiotensin II has been shown to be a
cytokine especially acting as a
growth factor. A local renin-angiotensin system has been identified in the prostate gland, and the physiologic function of
angiotensin II seems to be similar in
prostate cancer, as we previously reported. In the present study, we explored the biological role of
angiotensin II in oxidative stress of
prostate cancer cells. Activated Akt was determined, and the expression of oxidative stress-related
proteins (p47phox,
manganese superoxide dismutase 2,
glutathione peroxidase) was examined by Western blotting in LNCaP cells, which were stimulated with
angiotensin II and/or an
angiotensin II receptor type 1 blocker,
candesartan. To examine DNA damage induced by
angiotensin II,
8-hydroxy-2'-deoxyguanosine was determined, and Western blots were analyzed to detect checkpoint
proteins including p53, Chk2, and cdc2. Immunocytochemical studies of
inducible nitric oxide synthase and
superoxide anion radical (O(2)(-)) were done in LNCaP cells stimulated with
angiotensin II. The phosphorylation of Akt was induced by
angiotensin II treatment and inhibited by
candesartan, as well as by
LY294002, an inhibitor of
phosphoinositide 3-kinase. Oxidative stress-related
proteins were up-regulated by
angiotensin II and inhibited by pretreatment with
candesartan or
catalase. The level of
8-hydroxy-2'-deoxyguanosine was increased by
angiotensin II and conversely decreased by
candesartan. Immunocytochemical studies showed that
angiotensin II enhanced an inflammatory marker,
inducible nitric oxide synthase, and the production of O(2)(-) radical. The hypothesis that
angiotensin II has the potential to induce oxidative stress, which may be implicated in
carcinogenesis of the prostate gland through long-term exposure to chronic
inflammation is proposed.