Over-expression of angiotensin II type 2 receptor gene induces cell death in lung adenocarcinoma cells

Abstract

The endogenous angiotensin II (Ang II) type 2 receptor (AT2) has been shown to mediate apoptosis in cardiovascular tissues. Thus, the aim of this study was to explore the anti-cancer effect of AT2 over-expression on lung adenocarcinoma cells in vitro using adenoviral (Ad), FuGENE, and nanoparticle vectors. All three gene transfection methods efficiently transfected AT2 cDNA into lung cancer cells but caused minimal gene transfection in normal lung epithelial cells. Ad-AT2 significantly attenuated multiple human lung cancer cell growth (A549 and H358) as compared to the control viral vector, Ad-LacZ, when cell viability was examined by direct cell count. Examination of annexin V by flow cytometry revealed the activation of the apoptotic pathway via AT2 over-expression. Western Blot analysis confirmed the activation of caspase-3. Similarly, poly (lactide-co-glycolic acid) (PLGA) biodegradable nanoparticles encapsulated AT2 plasmid DNA were shown to be effectively taken up into the lung cancer cell. Nanoparticle-based AT2 gene transfection markedly increased AT2 expression and resultant cell death in A549 cells. These results indicate that AT2 over-expression effectively attenuates growth of lung adenocarcinoma cells through intrinsic apoptosis. Our results also suggest that PLGA nanoparticles can be used as an efficient gene delivery vector for lung adenocarcinoma targeted therapy.

Angiotensin-converting enzyme 2 attenuates the metastasis of non-small cell lung cancer through inhibition of epithelial-mesenchymal transition

“…In recent years, the role of the renin-angiotensin system (RAS) in tumor progression or metastasis has been extensively characterized (3)(4)(5)(6)(7)(8). Changes in the expression of RAS components, particularly in local tumor tissue, appear to correlate with tumor grade and clinical outcome (9).…”

2010 Position Paper of the Italian Society of Hypertension (SIIA)

“…In addition, pancreatic ductal carcinoma cells, placed in culture with fibroblasts transfected with the AT2 receptors, showed a slower growth rate, whereas overexpression of AT2 receptors in lung cancer cells induced cell death via apoptosis. [11,12] These data seem to support an antitumour profile by AT2 receptors. Recent experimental data, however, have demonstrated that, under certain pathological conditions, AT2 receptors may play an AT1 phenotype, losing their properties of vasodilation and antiangiogenesis and assuming a pro-angiogenic property.…”

Hypoxia induces dysregulation of local renin-angiotensin system in mouse Lewis lung carcinoma cells

“…AT2R over-expression effectively attenuates the growth of lung adenocarcinoma cells through intrinsic apoptosis (Pickel et al, 2010). However, AT2R may also promote tumorigenesis and cell proliferation (Kanehira et al, 2005;Pickel et al, 2010). Thus, the potential role of hypoxia-induced RAS dysregulation should be examined.…”

“…ANG II promotes tumor proliferation, migration, angiogenesis, and metastasis primarily through AT1R (Egami et al, 2003;Fujita et al, 2002Fujita et al, , 2005. AT2R may counter the activities of AT1R (Pickel et al, 2010). However, AT2R can also promote tumor angiogenesis (Pickel et al, 2010) and proliferation (Kanehira et al, 2005).…”

“…AT2R may counter the activities of AT1R (Pickel et al, 2010). However, AT2R can also promote tumor angiogenesis (Pickel et al, 2010) and proliferation (Kanehira et al, 2005). In addition, the RAS includes ACE2 (Fleming et al, 2005), which converts ANG I or ANG II to angiotensin 1-7 (ANG 1-7).…”