Hypercapnic tumor microenvironment confers chemoresistance to lung cancer cells by reprogramming mitochondrial...

The tumor microenvironment has previously been reported to be hypercapnic (as high as ~84 mmHg), although its effect on tumor cell behaviors is unknown. In this study, high CO₂ levels, ranging from 5% to 15%, protected lung cancer cells from anticancer agents, such as cisplatin, carboplatin and etoposide, by suppressing apoptosis. The cytoprotective effect of a high CO₂ level was independent of acidosis and was due to mitochondrial metabolic reprogramming that reduced mitochondrial respiration, as assessed by oxygen consumption, oxidative phosphorylation, mitochondrial membrane and oxidative potentials, eventually leading to reduced reactive oxidant species production. In contrast, high CO₂ levels did not affect cisplatin-mediated DNA damage responses or the expression of Bcl-2 family proteins. Although high CO₂ levels inhibited glycolysis, this inhibition was not mechanistically involved in high CO₂-mediated reductions in mitochondrial respiration, because a high CO₂ concentration inhibited isolated mitochondria. A cytoprotective effect of high CO₂ levels on mitochondria DNA-depleted cells was not noted, lending support to our conclusion that high CO₂ levels act on mitochondria to reduce the cytotoxicity of anticancer agents. High CO₂-mediated cytoprotection was also noted in a 3D culture system. In conclusion, the hypercapnic tumor microenvironment reprograms mitochondrial respiratory metabolism causing chemoresistance in lung cancer cells. Thus, tumor hypercapnia may represent a novel target to improve chemosensitivity.