Potential of Curcumin and Quercetin in Modulation of Premature Mitochondrial Senescence and Related Changes during Lung Carcinogenesis.

Abstract

Ferroptosis is a classification of programmed cell death, which activates oxidative cell death in an iron and lipid peroxides-dependent manner. Targeting ferroptosis is a novel therapeutic approach for cancer therapy. Lung cancer is the leading cause of cancer related deaths all over the world. Circular RNAs (circRNAs), as a form of noncoding RNAs with a specific closed circular sequence are emerging as a new field in cancer research. However, the regulatory mechanisms of circRNAs in ferroptosis during lung cancer development are still elusive. In this work, we elucidate the potential prognostic value and the crucial role of circular RNA circFOXP1 in ferroptosis of lung cancer. We found that the expression of circFOXP1 was remarkably up-regulated in clinical lung sample tissues compared with adjacent tissues. The up-regulation of circFOXP1 was closely correlated with the poor overall survival of lung cancer patients. The knockdown of circFOXP1 suppressed the cell viability of lung cancer cells. The colony formation counts of lung cancer cells were repressed by the depletion of circFOXP1 as well. The Edu-positive lung cancer cells were attenuated by the silencing of circFOXP1. The migration and invasion of lung cancer cells were suppressed by circFOXP1 short hairpin RNA (shRNA). The expression of E-cadherin was enhanced, and vimentin expression was reduced by the knockdown of circFOXP1. Moreover, the treatment of ferroptosis activator erastin or RSL3 repressed the cell viability of lung cancer cells and the overexpression of circFOXP1 rescued the phenotype. The levels of malondialdehyde (MDA), iron, and lipid reactive oxygen species (ROS) were enhanced by the silencing of circFOXP1 in both erastin and RSL3-stimulated lung cancer cells. Mechanically, circFOXP1 increased SLC7A11 expression by directly sponging miR-520a-5p in lung cancer cells. The inhibitor of miR-520a-5p or the overexpression of SLC7A11 reversed circFOXP1 shRNA-induced ferroptosis phenotypes in lung cancer cells. Importantly, circFOXP1 contributed to tumor growth of lung cancer cells by enhancing SLC7A11 in vivo. Collectively, we concluded that circular RNA circFOXP1 is a potential diagnostic biomarker and contributes to malignant progression by repressing ferroptosis of lung cancer. Targeting circFOXP1 may be served as a promising therapeutic approach for lung cancer.