Suppressed mitochondrial respiration via NOX5-mediated redox imbalance contributes to the antitumor activity of anlotinib in oral squamous cell carcinoma

作     者：Zhexun Huang Qiao Su Wuguo Li Hui Ren Huiqiang Huang Anxun Wang Zhexun Huang;Qiao Su;Wuguo Li;Hui Ren;Huiqiang Huang;Anxun Wang

作者机构：Department of Oral and Maxillofacial SurgeryThe First Affiliated HospitalSun Yat-Sen UniversityGuangzhouGuangdong 510080China Animal Experiment CenterThe First Affiliated HospitalSun Yat-Sen UniversityGuangzhouGuangdong 510080China Department of Medical OncologySun Yat-sen University Cancer CenterGuangzhouGuangdong 510060China State Key Laboratory of Oncology in South ChinaGuangzhouGuangdong 510060China Collaborative Innovation Center for Cancer MedicineGuangzhouGuangdong 510060China 

出 版 物：《Journal of Genetics and Genomics》 (遗传学报（英文版）)

年 卷 期：2021年第48卷第7期

页      面：582-594页

核心收录：

学科分类：0710[理学-生物学] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 10[医学] 

基　　金：supported by funding from the National Natural Science Foundation of China(NSFC 81672659)。 

主　　题：Anlotinib Oral squamous cell carcinoma NOX5 Oxidative stress Oxidative phosphorylation Mitochondrial respiration function 

摘      要：Anlotinib,a novel multitarget tyrosine kinase inhibitor,has shown promising results in the management of various carcinomas.This study aimed to investigate the antitumor activity of anlotinib in oral squamous cell carcinoma(OSCC)and the underlying molecular mechanism.A retrospective clinical study revealed that anlotinib improved the median progression-free survival(m PFS)and median overall survival(m OS)of patients with recurrent and metastatic(R/M)OSCC,respectively.Functional studies revealed that anlotinib markedly inhibited in vitro proliferation of OSCC cells and impeded in vivo tumor growth of OSCC patientderived xenograft models.Mechanistically,RNA-sequencing identified that oxidative stress,oxidative phosphorylation and AKT/m TOR signaling were involved in anlotinib-treated OSCC cells.Anlotinib upregulated NADPH oxidase 5(NOX5)expression,elevated reactive oxygen species(ROS)production,impaired mitochondrial respiration,and promoted apoptosis.Moreover,anlotinb also inhibited phosphoAkt(p-AKT)expression and elevated p-e IF2αexpression in OSCC cells.NOX5 knockdown attenuated these inhibitory effects and cytotoxicity in anlotinib-treated OSCC cells.Collectively,we demonstrated that anlotinib monotherapy demonstrated favorable anticancer activity and manageable toxicities in patients with R/M OSCC.The antitumor activity of anlotinib in OSCC may be mainly involved in the suppression of mitochondrial respiration via NOX5-mediated redox imbalance and the AKT/e IF2αpathway.