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Volume 48 Issue 7
Jul.  2021
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Article Navigation >  Journal of Genetics and Genomics  > 2021  >  48(7): 582-594

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

doi: 10.1016/j.jgg.2021.06.014
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    a Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China;

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    b Animal Experiment Center, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China;

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    c Department of Medical Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, China;

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    d State Key Laboratory of Oncology in South China, Guangzhou, Guangdong 510060, China;

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    e Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, China

Funds:

This work was supported by funding from the National Natural Science Foundation of China (NSFC 81672659).

  • Received Date: 2021-04-16
  • Accepted Date: 2021-06-23
  • Rev Recd Date: 2021-06-19
  • Publish Date: 2021-07-20
    Abstract

  • 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 (mPFS) and median overall survival (mOS) 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 patient-derived xenograft models. Mechanistically, RNA-sequencing identified that oxidative stress, oxidative phosphorylation and AKT/mTOR 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 phospho-Akt (p-AKT) expression and elevated p-eIF2α expression 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/eIF2α pathway.

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