title: Hypoxia-induced angiotensin II by the lactate-chymase-dependent mechanism mediates radioresistance of hypoxic tumor cells.
abstract: The renin-angiotensin system (RAS) is a principal determinant of arterial blood pressure and fluid and electrolyte balance. RAS component dysregulation was recently found in some malignancies and correlated with poor patient outcomes. However, the exact mechanism of local RAS activation in tumors is still unclear. Here, we find that the local angiotensin II predominantly exists in the hypoxic regions of tumor formed by nasopharyngeal carcinoma CNE2 cells and breast cancer MDA-MB-231 cells, where these tumor cells autocrinely produce angiotensin II by a chymase-dependent rather than an angiotensin converting enzyme-dependent mechanism. We further demonstrate in nasopharyngeal carcinoma CNE2 and 5-8F cells that this chymase-dependent effect is mediated by increased levels of lactate, a by-product of glycolytic metabolism. Finally, we show that the enhanced angiotensin II plays an important role in the intracellular accumulation of HIF-1α of hypoxic nasopharyngeal carcinoma cells and mediates the radiation-resistant phenotype of these nasopharyngeal carcinoma cells. Thus, our findings reveal the critical role of hypoxia in producing local angiotensin II by a lactate-chymase-dependent mechanism and highlight the importance of local angiotensin II in regulating radioresistance of hypoxic tumor cells.
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Guozhu
authors.initials: G
authors.lastname: Xie
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Department of Radiation Oncology, Teaching Hospital of Fujian Provincial Cancer Hospital, Fuzhou, Fujian 350014, P.R. China.
authors.forename: Qiwei
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zheng
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Lanfang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Jie
authors.initials: J
authors.lastname: Lin
authors.affiliation: Breast Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Zhaoze
authors.initials: Z
authors.lastname: Guo
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Shasha
authors.initials: S
authors.lastname: Du
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.
authors.forename: Chen
authors.initials: C
authors.lastname: Ren
authors.affiliation: Jules Stein Eye Institute, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Quan
authors.initials: Q
authors.lastname: Yuan
authors.affiliation: Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.|Department of Radiation Oncology, Cancer Center of Guangzhou Medical University, Guangzhou, Guangdong 510095, P.R. China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Yuan
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D053818:Chymases / Q000378:metabolism*; D005260:Female; D006863:Hydrogen-Ion Concentration; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019344:Lactic Acid / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D007703:Peptidyl-Dipeptidase A / Q000378:metabolism; D011836:Radiation Tolerance; D012084:Renin-Angiotensin System; D059016:Tumor Microenvironment
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000804:Angiotensin II; D019344:Lactic Acid; D007703:Peptidyl-Dipeptidase A; D053818:Chymases