angiotensin-i and Carcinoma--Non-Small-Cell-Lung

Renin-angiotensin system (RAS) signaling has been implicated in the development of cancer. The new RAS ACE2/Ang-(1-7)/Mas axis antagonizes the classical ACE/Ang II/AT1R axis. Ang-(1-7) has pleiotropic roles in lung cancer including suppressing proliferation, angiogenesis, and metastasis. This research was designed to investigate the effect of Ang-(1-7) on tumor-associated angiogenesis in DDP-resistant lung cancer cell lines. We first established acquired DDP-resistant cell lines A549 (A549-DDP) and LLC (LLC-DDP). We next performed RT-qPCR, western blot, ELISA, tube formation, microvessel density detection, immunohistochemistry, and tumor formation assays. The results showed that the mRNA and protein levels of RAS components and vascular endothelial growth factor A (VEGFa) were lessened in the A549/LLC-DDP+Ang-(1-7) group compared with the A549/LLC-DDP group. This effect could be blocked by the MAS receptor antagonist A779. The data revealed that Ang-(1-7) could perform its antiangiogenic function by PI3K/AKT and MAPK pathways. Furthermore, the impact of Ang-(1-7) on tumor-associated angiogenesis has been confirmed in lung cancer xenograft model with acquired DDP resistance. These results provide a theoretical basis for designing therapeutic strategies for targeting Ang-(1-7) in the treatment of NSCLC.

Topics: Angiotensin I; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Peptide Fragments; Phosphatidylinositol 3-Kinases; Platinum; Vascular Endothelial Growth Factor A

Ang-(1-7) inhibits lung cancer cell growth both in vitro and in vivo. However, the molecular mechanism of action is unclear and also the rapid degradation of Ang-(1-7) in vivo limits its clinical application. Here, we have demonstrated that Ang- (1-7) inhibits lung cancer cell growth by interrupting pre-replicative complex assembly and restrains epithelial-mesenchymal transition via Cdc6 inhibition. Furthermore, we constructed a mutant adeno-associated viral vector AAV8 (Y733F) that produced stable and high efficient Ang-(1-7) expression in a xenograft tumor model. The results show that AAV8-mediated Ang-(1-7) over-expression can remarkably suppress tumor growth in vivo by down-regulating Cdc6 and anti-angiogenesis. Ang-(1-7) over-expression via the AAV8 method may be a promising strategy for lung cancer treatment.

Topics: Angiotensin I; Animals; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; Cell Movement; Cell Proliferation; Dependovirus; DNA Replication; Down-Regulation; Epithelial-Mesenchymal Transition; Female; Genetic Vectors; Humans; Immunohistochemistry; Lung; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Nude; Multienzyme Complexes; Neovascularization, Pathologic; Nuclear Proteins; Peptide Fragments; Proteolysis; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays