Antiproliferative activity of angiotensin II receptor blocker through cross-talk between stromal and epithelial prostate cancer cells

Abstract

We showed previously that angiotensin II activated the proliferation of prostate cancer cells and that angiotensin II receptor blockers (ARB) could inhibit it. Here, we investigated whether angiotensin II exerts mitogenic effects on the cross-talk between stromal and cancer cells and whether an ARB can inhibit tumor growth through actions on stromal cells. Cell proliferation and interleukin-6 secretion of prostate stromal PrSC cells stimulated with angiotensin II, tumor necrosis factor-A, or epidermal growth factor were examined in the absence and presence of ARB. We examined the effect of ARB on mitogenactivated protein kinase (MAPK) phosphorylation of PrSC and PC-3 cells treated with conditioned medium of PrSC cells and determined the effect of ARB on tumor growth induced by paracrine factors from PrSC cells. Angiotensin II activated the cell proliferation and interleukin-6 secretion of PrSC cells, and ARB inhibited it. Angiotensin II, tumor necrosis factor-A, or epidermal growth factor induced MAPK phosphorylation in PrSC cells, and this phosphorylation was inhibited by ARB. Conditioned medium of PrSC cells with angiotensin II activated MAPK phosphorylation in PC-3 cells, and ARB-treated conditioned medium of PrSC cells inhibited it. The tumor growth and angiogenesis of a mixture of PC-3 with PrSC were inhibited by ARB administration, whereas those of PC-3 xenografts were not inhibited. ARB exerted an antiproliferative effect on prostate cancer through paracrine factors from stromal cells. Because prostate stromal cells are thought to be involved in the initiation and development of prostate cancer, the present data suggest the possibility that ARBs are a novel therapeutic class of agents for prostate cancer.

Naftopidil, a Selective α1-Adrenoceptor Antagonist, Suppresses Human Prostate Tumor Growth by Altering Interactions between Tumor Cells and Stroma

“…In PrSC, mRNA expressions of FGF-2 and FGF-7 were detected (data not shown). Previous report showed that responsiveness of E9 cells to FGF-2 and and IL-6 secretion from PrSC (15). It is highly important that naftopidil shows antiproliferative effects not only on cancer cells but also on stromal cells, and that stromal cell growth was inhibited by lower concentrations than that required to inhibit cancer cells.…”

“…Olumi et al demonstrated stroma-induced malignant transformation, indicating that fibroblasts surrounding epithelia play an important role in PCa development (14). Other groups reported that coinoculation of PCa cells with fibroblasts increased tumorigenicity and implied the promotion of angiogenesis (11,15,16). Therefore, the inhibition of tumor-stroma interactions with addition of the suppression of cancer cell growth might lead to synergistic effects on tumor control.…”

Angiotensin II Induces Oxidative Stress in Prostate Cancer

“…We previously clarified that angiotensin II acted as a growth factor in prostate cancer and stromal cells (14,16). Interestingly, earlier investigators have reported that angiotensin II induced oxidative stress in vascular cells, for example, demonstrating that angiotensin II stimulated the production of ROS in endothelial cells by up-regulating the subunits of NADPH oxidases (17,18).…”

“…Previously, we have reported that angiotensin II facilitates the secretion of some growth factors and cytokines from prostate stromal cells, resulting in cell proliferation of prostate cancer (16). Given that angiotensin II induces oxidative stress in vascular cells, it is very interesting to speculate that angiotensin II may function as an inducer of oxidative stress implicated in carcinogenesis.…”

“…Angiotensin II activates the signal transduction of mitogen-activated protein kinase and signal transducers and activators of transcription 3 and angiogenesis in prostate cancer cells (15). Also, angiotensin II facilitates the secretion of some growth factors and cytokines from prostate stromal cells, resulting in cell proliferation of prostate cancer (16). Of interest, many investigators have clarified that angiotensin II induces oxidative stress in vascular cells.…”