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.
Highlights
The renin-angiotensin system (RAS) is classically known as a circulating or hormonal system that regulates blood pressure and electrolyte and fluid homeostasis[1]
To determine whether hypoxia contributes to the generation of angiotensin II (Ang II) in tumor cells, we first measured the Ang II levels in the supernatant of in vitro cultured tumor cells from CNE1, CNE2 and 5–8F nasopharyngeal carcinoma cells and MDA-MB-231 breast cancer cells, both of which display predominant hypoxia in their solid tumors[17,18]
Analysis of an enzyme-linked immunosorbent assay (ELISA) showed that only low levels of Ang II were detected in the supernatant of tumors cells from all these cell lines when cultured under normoxic (20% O2) conditions
Summary
The renin-angiotensin system (RAS) is classically known as a circulating or hormonal system that regulates blood pressure and electrolyte and fluid homeostasis[1]. In addition to the circulating RAS, local tissue RAS has been increasingly found in diverse organ systems, including the kidney, heart, vasculature, pancreas, and adipose tissue[3] In these tissues, angiotensinogen, renin, ACE and Ang II receptors are invariably locally synthesized and local Ang II functions in an autocrine or paracrine manner and participates in organ homeostasis and the pathogenesis of chronic diseases[3]. Previous studies have shown that Ang II can be locally produced in hypoxic somatic tissues and that this Ang II overproduction plays an important role in the development of chronic disease, such as atherosclerosis[14], diabetic nephropathy[15], and retinopathy[16]. Our study reveals the critical role of hypoxia in producing local Ang II by a lactate-chymase dependent mechanism and highlights the important role of local Ang II in regulating radioresistance of tumor cells in the hypoxic microenvironment
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