Angiotensin II suppresses adriamycin-induced apoptosis through activation of phosphatidylinositol 3-kinase/Akt signaling in human breast cancer cells
Yanbin Zhao
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150040, China
Search for more papers by this authorXuesong Chen
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150040, China
Search for more papers by this authorLi Cai
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150040, China
Search for more papers by this authorYanmei Yang
Cancer Research Institute of Heilongjiang Province, Harbin 150040, China
Search for more papers by this authorCorresponding Author
Guangjie Sui
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150040, China
*Corresponding authors: Jin Wu: Tel, 86-451-86298730; E-mail, [email protected] Guangjie Sui: Tel, 86-451-86298279; E-mail, [email protected]Search for more papers by this authorCorresponding Author
Jin Wu
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150040, China
*Corresponding authors: Jin Wu: Tel, 86-451-86298730; E-mail, [email protected] Guangjie Sui: Tel, 86-451-86298279; E-mail, [email protected]Search for more papers by this authorYanbin Zhao
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150040, China
Search for more papers by this authorXuesong Chen
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150040, China
Search for more papers by this authorLi Cai
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150040, China
Search for more papers by this authorYanmei Yang
Cancer Research Institute of Heilongjiang Province, Harbin 150040, China
Search for more papers by this authorCorresponding Author
Guangjie Sui
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150040, China
*Corresponding authors: Jin Wu: Tel, 86-451-86298730; E-mail, [email protected] Guangjie Sui: Tel, 86-451-86298279; E-mail, [email protected]Search for more papers by this authorCorresponding Author
Jin Wu
Department of Medical Oncology, The Third Affiliated Hospital of Harbin Medical University, Harbin 150040, China
*Corresponding authors: Jin Wu: Tel, 86-451-86298730; E-mail, [email protected] Guangjie Sui: Tel, 86-451-86298279; E-mail, [email protected]Search for more papers by this authorAbstract
Angiotensin II (Ang II) stimulates tumor growth and angio-genesis in some solid cancer cells, but its anti-apoptosis role in breast cancer remains unclear. To address this issue, we investigated the effect of Ang II on adriamycin-induced apoptosis in breast cancer MCF-7 cells. Treatment of human breast cancer MCF-7 cells with adriamycin, a DNA topoisomerase IIα inhibitor, caused apoptosis. However, cells pretreated with Ang II were resistant to this apoptosis. Ang II significantly reduced the ratio of apoptotic cells and stimulation of phospho-Akt-Thr308 and phospho-Akt-Ser473 in a dose-dependent and time-dependent manner. In addition, Ang II significantly prevented apoptosis through inhibiting the cleavage of procaspase-9, a major downstream effector of Akt. TheAng II type 1 receptor (AT1R) was responsible for these effects. Among the signaling molecules downstream of AT1R, we revealed that the phosphatidylinositol 3-kinase/Akt pathway plays a predominant role in the anti-apoptotic effect of Ang II. Our data indicated that Ang n plays a critical anti-apoptotic role in breast cancer cells by a mechanism involving AT1R/phosphatidylinositol 3-kinase/Akt activation and the subsequent suppression of caspase-9 activation.
References
- 1 Touyz RM, Deng LY, He G, Wu XH, Schiffrin EL. Angiotensin II stimulates DNA and protein synthesis in vascular smooth muscle cells from human arteries: Role of extracellular signal-regulated kinases. J Hypertens 1999, 17: 907–916.
- 2 Everett AD, Heller F, Fisher A. AT1 receptor gene regulation in cardiac myocytes and fibroblasts. J Mol Cell Cardiol 1996, 28: 1727–1736.
- 3 Brilla CG, Scheer C, Rupp H. Renin-angiotensin system and myo-cardial collagen matrix: modulation of cardiac fibroblast function by angiotensin II type 1 receptor antagonism. J Hypertens Suppl 1997, 15: S13–S19.
- 4 Ino K, Uehara C, Kikkawa F, Kajiyama H, Shibata K, Suzuki T, Khin EE et al. Enhancement of aminopeptidase A expression during angiotensin II-induced choriocarcinoma cell proliferation through AT1 receptor involving protein kinase C- and mitogen-activated protein kinase-dependent signaling pathway. J Clin Endocrinol Metab 2003, 88: 3973–3982.
- 5 Muscella A, Greco S, Elia MG, Storelli C, Marsigliante S. Angiotensin II stimulation of Na+/K+ATPase activity and cell growth by calcium-independent pathway in MCF-7 breast cancer cells. Endocrinology 2002, 173: 315–323.
- 6 Suganuma T, Ino K, Shibata K, Kajiyama H, Nagasaka T, Mizutani S, Kikkawa F. Functional expression of the angiotensin II type 1 receptor in human ovarian carcinoma cells and its blockade therapy resulting in suppression of tumor invasion, angiogenesis, and peritoneal dissemination. Clin Cancer Res 2005, 11: 2686–2694.
- 7 Amaya K, Ohta T, Kitagawa H, Kayahara M, Takamura H, Fujimura T, Nishimura G et al. Angiotensin II activates MAP kinase and NF-kappaB through angiotensin II type I receptor in human pancreatic cancer cells. Int J Oncol 2004, 25: 849–856.
- 8 Thomas WG, Mendelsohn FA. Angiotensin receptors: form and distribution. Int J Biochem Cell Biol 2003, 35: 774–779.
- 9 Kosugi M, Miyajima A, Kikuchi E, Horiguchi Y, Murai M. Angiotensin II type 1 receptor antagonist candesartan as an angiogenic inhibitor in a xenograft model of bladder cancer. Clin Cancer Res 2006, 12: 2888–2893.
- 10 Fujimoto Y, Sasaki T, Tsuchida A, Chayama K. Angiotensin II type 1 receptor expression in human pancreatic cancer and growth inhibition by angiotensin II type 1 receptor antagonist. FEBS Lett 2001, 495: 197–200.
- 11 Egami K, Murohara T, Shimada T, Sasaki K, Shintani S, Sugaya T, Ishii M et al. Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J Clin Invest 2003, 112: 67–75.
- 12 Arrieta O, Guevara P, Escobar E, García-Navarrete R, Pineda B, Sotelo J. Blockage of angiotensin II type 1 receptor decreases the synthesis of growth factors and induces apoptosis in C6 cultured cells and C6 rat glioma. Br J Cancer 2005, 92: 1247–1252.
- 13 Greco S, Muscella A, Elia MG, Salvatore P, Storelli C, Mazzotta A, Manca C et al. Angiotensin II activates extracellular signal regulated kinases via protein kinase C and epidermal growth factor receptor in breast cancer cells. J Cell Physiol 2003, 196: 370–377.
- 14 Uemura H, Ishiguro H, Nakaigawa N, Nagashima Y, Miyoshi Y, Fujinami K, Sakaguchi A et al. Angiotensin II receptor blocker shows antiproliferative activity in prostate cancer cells: a possibility of tyrosine kinase inhibitor of growth factor. Mol Cancer Ther 2003, 2: 1139–1147.
- 15 Takahashi T, Taniguchi T, Konishi H, Kikkawa U, Ishikawa Y, Yokoyama M. Activation of Akt/protein kinase B after stimulation with angiotensin II in vascular smooth muscle cells. Am J Physiol 1999, 276: H1927–H1934.
- 16 Brader S, Eccles SA. Phosphoinositide 3-kinase signalling pathways in tumor progression, invasion and angiogenesis. Tumori 2004, 90: 2–8.
- 17 Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. Apoptosis 2004, 9: 667–676.
- 18 Datta SR, Brunet A, Greenberg ME. Cellular survival: a play in three Akts. Genes Dev 1999, 13: 2905–2927.
- 19 Kandel ES, Hay N. The regulation and activities of the multifunctional serine/threonine kinase Akt/PKB. Exp Cell Res 1999, 253: 210–229.
- 20
Cardone MH,
Roy N,
Stennicke HR,
Salvesen GS,
Franke TF,
Stanbridge E,
Frisch S
et al.
Regulation of cell death protease caspase-9 by phosphorylation.
Science
1998, 282: 318–321.
10.1126/science.282.5392.1318 Google Scholar
- 21 Datta SR, Dudek H, Tao X, Masters S, Fu H, Gotoh Y. Greenberg, ME. Akt phosphorylation of Bad couples survival signals to the cell-intrinsic death machinery. Cell 1997, 91: 231–241.
- 22 Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ et al. Akt promotes cell survival by phosphorylating and inhibiting a forkhead transcription factor. Cell 1999, 98: 857–866.
- 23 Inwang ER, Puddefoot JR, Brown CL, Goode AW, Marsigliante S, Ho MM, Payne JG et al. Angiotensin II type 1 receptor expression in human breast tissues. Br J Cancer 1997, 75: 1279–1283.
- 24 De Paepe B, Verstraeten VL, De Potter CR, Vakaet LA, Bullock GR. Growth stimulatory angiotensin II type-1 receptor is upregulated in breast hyperplasia and in situ carcinoma but not in invasive carcinoma. Histochem Cell Biol 2001, 116: 247–254.
- 25 Tahmasebi M, Puddefoot JR, Inwang ER, Goode AW, Carpenter R, Vinson GP. Transcription of the prorenin gene in normal and diseased breast. Eur J Cancer 1998, 34: 1777–1782.
- 26 Berry MG, Goode AW, Puddefoot JR, Vinson GP, Carpenter R. Integrin betal upregulation in MCF-7 breast cancer cells by angiotensin II. Eur J Surg Oncol 2000, 26: 25–29.
- 27 Ohashi H, Takagi H, Oh H, Suzuma K, Suzuma I, Miyamoto N, Uemura A et al. Phosphatidylinositol 3-kinase/Akt regulates angiotensin II-induced inhibition of apoptosis in microvascular endothe-lial cells by governing survivin expression and suppression of caspase-3 activity. Circ Res 2004, 94: 785–793.
- 28 Dugourd C, Gervais M, Corvol P, Monnot C. Akt is a major downstream target of PI3-kinase involved in angiotensin II-induced proliferation. Hypertension 2003, 41: 882–890.
- 29 Liu X, Shi Y, Giranda VL, Luo Y. Inhibition of the phosphatidylinositol 3-kinase/Akt pathway sensitizes MDA-MB468 human breast cancer cells to cerulenin-induced apoptosis. Mol Cancer Ther 2006, 5: 494–501.
- 30 Clark AS, West K, Streicher S, Dennis PA. Constitutive and induc-ible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 2002, 1: 707–717.
- 31 Gamen S, Anel A, Pérez-Galán P, Lasierra P, Johnson D, Piñeiro A, Naval J. Doxorubicin treatment activates a Z-VAD-sensitive caspase, which causes deltapsim loss, caspase-9 activity, and apoptosis in Jurkat cells. Exp Cell Res 2000, 258: 223–235.
