Quercetin inhibits DNA damage responses to induce apoptosis via SIRT5/PI3K/AKT pathway in non-small cell lung cancer

SIRT5 is a mitochondrial NAD+ -dependent lysine deacylase. Downregulation of SIRT5 has been linked to several primary cancers and DNA damage. In clinical therapy for non-small cell lung cancer (NSCLC), the Feiyiliu Mixture (FYLM) is an experience and effective Chinese herb prescription. And we found that quercetin is an important ingredient in the FYLM. However, whether quercetin regulates DNA damage repair (DDR) and induces apoptosis through SIRT5 in NSCLC remains unknown. The present study revealed that quercetin directly binds to SIRT5 and inhibits the phosphorylation of PI3K/AKT through the interaction between SIRT5 and PI3K, thus inhibiting the repair process of homologous recombination (HR) and non-homologous end-joining (NHEJ) in NSCLC, which raise mitotic catastrophe and apoptosis. Our study provided a novel mechanism of action of quercetin in the treatment of NSCLC. [Display omitted] •Quercetin induces NSCLC cell apoptosis mediated through inhibiting DDR and raising DNA damage accumulation.•Quercetin binding/overexpressing SIRT5 to inhibit PI3K/AKT signaling.•DDR inhibitors might provide an opportunity for better therapy for p53 mutated cancers.•Mitotic catastrophe is one of the consequences of DNA damage.