Functional angiotensin II type 2 receptors inhibit growth factor signaling in LNCaP and PC3 prostate cancer cell lines

Chow, Laurie T.C.; Rezmann, Linda Adriana; Imamura, Kiichi; Wang, L; Catt, Kevin J.; Tikellis, Christos; Louis, William J.; Frauman, Albert G; Louis, Simon N.S.

doi:10.1002/pros.20738

Cited by 37 publications

(45 citation statements)

References 24 publications

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“…With regard to the prostate, there is clear evidence of a tissue-based renin-angiotensin system within this gland and studies to date indicate beneficial actions of blocking AT1R and activating AT2R (15,(20)(21)(22)(23). For example, AT1R inhibitors decrease the growth of some prostate cancer cell lines and delay the development of prostate cancer, whereas AT2R inhibitors are present and have the ability to inhibit epidermal growth factor-induced prostate cancer cell growth in LNCaP and fast-growing androgen-independent PC3 cell lines (24). Increased expression of AT2R induces apoptosis in numerous cell lines, such as pheochromocytoma, fibroblasts, smooth muscle cells, and endothelial cells, with either Ang II-dependent or Ang II-independent regulation (25)(26)(27)(28)(29)(30)(31)(32).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2009

Molecular Cancer Therapeutics

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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-

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Section: Introductionmentioning

confidence: 99%

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

et al. 2009

Molecular Cancer Therapeutics

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“…These results suggest that neoplastic cells derived from prostate epithelial cells generally show an increased expression of both ATIP isomers and the results are consistent with our results in human malignancies (Table 1). The reason for low ATIP1 mRNA levels in PC3 cells is uncertain but this cell line also demonstrates low levels of functional AT 1 -receptors [2,4] and it is tempting to speculate that the two findings are related.…”

Section: Resultsmentioning

confidence: 99%

“…Our earlier in vitro studies clearly indicate that in spite of the presence of relatively low levels of AT 2 -receptor mRNA, activation of the AT 2 -receptor significantly inhibited EGF-induced LNCaP and PC3 cell growth [2]; in the absence of AT 2 -receptor activation, ATIP mRNA expression decreased when the cells were stimulated with EGF [10]; and that AT 2 -receptor activation inhibited the EGF-induced down-regulation of ATIP mRNA. These studies, in combination with the work described previously in this section, indicate that EGF may stimulate prostatic cell growth, at least in part, by reducing the levels of ATIP present in the cells and that activation of the AT 2 -receptor may prevent this down-regulation from occurring, thus suggesting that an important interaction exists between ATIP and the AT 2 -receptor in mediating prostate cancer cell growth.…”

Section: Resultsmentioning

confidence: 99%

The Expression of MTUS1/ATIP and Its Major Isoforms, ATIP1 and ATIP3, in Human Prostate Cancer

Louis

Chow

Varghayee

et al. 2011

Cancers

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Angiotensin II (Ang II), the main effector of the renin angiotensin system, acts upon two distinct transmembrane receptors, the Ang II type 1 and the type 2 (AT2-) receptor, to induce promotion and inhibition of ERK2 phosphorylation. The AT2-receptor, through an interaction with its putative signaling partner MTUS1/ATIP (AT2-receptor interacting protein), inhibits the mitogenic effects of EGF in prostate cancer cell lines representing both early and late stage disease. This is the first report on the expression of ATIP in normal and malignant human prostatic biopsies. The expression of ATIP and its major isoforms, ATIP1 and ATIP3, in normal prostatic cells and three prostate cancer cell lines was examined using QPCR and immunohistochemistry. Human biopsies containing benign prostatic hyperplasia (BPH), high grade prostatic intraepithelial neoplasia (HGPIN) and well, moderately and poorly differentiated prostate cancer were also examined. Overall, ATIP1 and ATIP3 mRNA expression was increased in malignant compared to normal tissues and cell lines. ATIP immunostaining was low or absent in both the basal and columnar epithelial cell layers surrounding BPH acini; however, it was observed in high concentration in neoplastic epithelial cells of HGPIN and was clearly evident in cytoplasms of malignant cells in all prostate cancer grades. ATIP immunostaining was also identified in the cytoplasms of LNCaP and PC3 prostate cancer cells. As the AT2-receptor/ATIP inhibitory signaling pathway exists in malignant cells in all grades of prostate cancer, enhancement of this pathway may be a therapeutic target even after the development of androgen-independence.

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“…The experimental and clinical studies clearly showed that sunitinib mainly acts by inhibiting VEGFR2 activation on endothelial cells [21] which triggers a negative feedback in tumours leading to a VEGF-A oversecretion [24]. Moreover, AT1-R blockers have been described to inhibit VEGF-A secretion by tumour cells [25] and decrease tumor angiogenesis [22, 26] as well as tumour cell proliferation [27]. AT1-R antagonists could also trigger cancer cell apoptosis [28].…”

Section: Discussionmentioning

confidence: 99%

Sunitinib Combined with Angiotensin-2 Type-1 Receptor Antagonists Induces More Necrosis: A Murine Xenograft Model of Renal Cell Carcinoma

Verhoest

Dolley-Hitze

Jouan

et al. 2014

BioMed Research International

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Background. Angiotensin-2 type-1 receptor antagonists not are only antihypertensive drugs but also can inhibit VEGF production. We hypothesised that adding telmisartan to sunitinib could potentiate the antiangiogenic effects. Material and Methods. 786-O cell lines were injected in nude mice. After tumor development, mice were divided into 4 groups: the first was the control group (DMSO), the second group was treated with sunitinib alone, the third group was treated with telmisartan alone, and the fourth group was treated with the combination. Drugs were orally administered every day for four weeks. Animals were sacrificed after treatment. Blood and tumor tissues were collected for analysis by immunohistochemistry, Western Blot, and ELISA methods. Results. All animals developed a ccRCC and ten in each group were treated. Using a kinetic model, tumors tended to grow slower in the combination group compared to others (P = 0.06). Compared to sunitinib alone, the addition of telmisartan significantly increased tissue necrosis (P = 0.038). Central microvascular density decreased (P = 0.0038) as well as circulating VEGF (P = 0.003). There was no significant variation in proliferation or apoptosis markers. Conclusion. The combination of sunitinib and telmisartan revealed an enhancement of the blockage of the VEGF pathway on renal tumor resulting in a decrease in neoangiogenesis and an increase in necrosis.

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Functional angiotensin II type 2 receptors inhibit growth factor signaling in LNCaP and PC3 prostate cancer cell lines

Abstract: Functional AT(2)-receptors are present and have the capacity to inhibit EGF-induced prostate cancer cell growth in LNCaP and fast growing androgen-independent PC3 cell lines, whereas functional AT(1)-receptors are found only in LNCaP cells where their activation stimulates DNA synthesis.

Cited by 37 publications

References 24 publications

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

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

The Expression of MTUS1/ATIP and Its Major Isoforms, ATIP1 and ATIP3, in Human Prostate Cancer

Sunitinib Combined with Angiotensin-2 Type-1 Receptor Antagonists Induces More Necrosis: A Murine Xenograft Model of Renal Cell Carcinoma

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