Angiotensin II activates extracellular signal regulated kinases via protein kinase C and epidermal growth factor receptor in breast cancer cells

Abstract

Angiotensin II (Ang II) induces, through AT1, intracellular Ca(2+) increase in both normal and cancerous breast cells in primary culture (Greco et al., 2002 Cell Calcium 2:1-10). We here show that Ang II stimulated, in a dose-dependent manner, the 24 h-proliferation of breast cancer cells in primary culture, induced translocation of protein kinase C (PKC)-alpha, -beta1/2, and delta (but not -epsilon, -eta, -theta, -zeta, and -iota), and phosphorylated extracellular-regulated kinases 1 and 2 (ERK1/2). The proliferative effects of Ang II were blocked by the AT1 antagonist, losartan. Also epidermal growth factor (EGF) had mitogenic effects on serum-starved breast cancer cells since induced cell proliferation after 24 h and phosphorylation of ERK1/2. The Ang II-induced proliferation of breast cancer cells was reduced by (a) Gö6976, an inhibitor of conventional PKC-alpha and -beta1, (b) AG1478, an inhibitor of the tyrosine kinase of the EGF receptor (EGFR), and (c) downregulation of 1,2-diacylglycerol-sensitive PKCs achieved by phorbol 12-myristate 13-acetate (PMA). A complete inhibition of the Ang II-induced cell proliferation was achieved using the inhibitor of the mitogen activated protein kinase kinase (MAPKK or MEK), PD098059, or using Gö6976 together with AG1478. These results indicate that in human primary cultured breast cancer cells AT1 regulates mitogenic signaling pathways by two simultaneous mechanisms, one involving conventional PKCs and the other EGFR transactivation.

Local angiotensin II-generation in human gastric cancer: Correlation with tumor progression through the activation of ERK1/2, NF-κB and survivin

“…Therefore, considerable attention has been focused on the development of RAS blockade therapy as a new strategy for cancer treatment (8)(9)(10)(11)(12)(13)(14)(15)(16)30).…”

“…GPCR -epidermal growth factor receptor (EGFR) cross-talk pathways are widely established and it has been reported that stimulation of angiotensin II involves transactivation of the EGFR, resulting in the activation of the MAPK pathway in various cell types (16,(41)(42)(43)(44)(45).…”

“…Lever et al reported the first clinical evidence that a long-term angiotensin II blockade might have a protective effect against carcinogenesis (17). There is increasing evidence that angiotensin II is involved in tumor biology and the potential anti-tumor effect of angiotensin II type 1 (AT1) receptor antagonist in tumors expressing AT1 receptor (8)(9)(10)(11)(12)(13)(14)(15)(16). Hence, the blockade of angiotensin II has been considered a noteworthy molecular targeted therapy in recent years.…”

Decreased Expression of Angiotensin-Converting Enzyme 2 in Pancreatic Ductal Adenocarcinoma Is Associated with Tumor Progression

“…ANG II, the biologically active peptide of the RAS, is a major regulator of blood pressure and cardiovascular homeostasis, and is also recognized as a potent mitogen (Deshayes and Nahmias 2005). Recently, it has been shown that ANG II is involved in the regulation of cell proliferation, migration, inflammation, and tissue remodeling, as well as angiogenesis via the ANG II type 1 receptor (AT1R), (Greco et al 2003;Uemura et al 2003). These findings have suggested that the ACE-ANG II-AT1R pathway might be related to cancer biology (Deshayes and Nahmias 2005;Neo et al 2007).…”

Polymorphism of RAS in Patients with AT1-AA Mediated Steroid Refractory Acute Rejection

“…Angiotensin II has been proven to have growth factor-like and angiogenic activities [41] and these activities are mediated through the activation of the angiotensin type 1 receptor [42]. The AGT1R A1166C polymorphism was found to predict the systemic and renal response to angiotensin receptor antagonism and angiotensin II infusion in healthy subjects [43].…”