title: ACE2 overexpression inhibits acquired platinum resistance-induced tumor angiogenesis in NSCLC.
abstract: Angiotensin II (AngII) is a multifunctional bioactive peptide in the renin-angiotensin system (RAS). Angiotensin-converting enzyme 2 (ACE2) is a newly identified component of RAS. We previously reported that ACE2 overexpression may inhibit cell growth and vascular endothelial growth factor (VEGF) production in vitro and in vivo. In the present study, we investigated the effect of ACE2 on tumor-associated angiogen-esis after the development of acquired platinum resistance in non-small cell lung cancer (NSCLC). Four NSCLC cell lines, A549, LLC, A549-DDP and LLC-DDP, were used in vitro, while A549 and A549-DDP cells were used in vivo. A549-DDP and LLC-DDP cells were newly established at our institution as acquired platinum-resistant sublines by culturing the former parent cells in cisplatin (CDDP)-containing conditioned medium for 6 months. These platinum-resistant cells showed significantly higher angiotensin II type 1 receptor (AT1R), ACE and VEGF production and lower ACE2 expression than their corresponding parent cells. We showed that ACE2 overexpression inhibited the production of VEGF in vitro and in vivo compared to their corresponding parent cells. We also found that ACE2 overexpression reduced the expression of AT1R and ACE. Additionally, we confirmed that ACE2 overexpres-sion inhibited cell growth and VEGF production while simultaneously suppressing ACE and AT1R expression in human lung cancer xenografts. Our findings indicate that ACE2 overexpression may potentially suppress angiogenesis in NSCLC after the development of acquired platinum resistance.
authors.affiliation: Department of Respiration, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China.
authors.forename: Qijian
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: Department of Respiration, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Respiration, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China.
authors.forename: Jianping
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Respiration, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China.
authors.forename: Huanying
authors.initials: H
authors.lastname: Wan
authors.affiliation: Department of Respiration, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China.
authors.forename: Qingyun
authors.initials: Q
authors.lastname: Li
authors.affiliation: Department of Respiration, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200025, P.R. China.
authors.forename: Yun
authors.initials: Y
authors.lastname: Feng
mesh_terms: D000072283:A549 Cells; D000804:Angiotensin II / Q000235:genetics; D000085962:Angiotensin-Converting Enzyme 2; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000009:adverse effects / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D009944:Organoplatinum Compounds / Q000009:adverse effects* / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000235:genetics*; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
chemical_list: D009944:Organoplatinum Compounds; D044140:Receptor, Angiotensin, Type 1; D042461:Vascular Endothelial Growth Factor A; D000804:Angiotensin II; D007703:Peptidyl-Dipeptidase A; C000705307:ACE2 protein, human; C000705328:Ace2 protein, mouse; D000085962:Angiotensin-Converting Enzyme 2; D002945:Cisplatin