Teniposide Triggers DNA Repair Inhibition by Binding and Ubiquitination of Apurinic/Apyrimidinic Endonuclease 1 to Boost Oxidative DNA Damage for Lung Cancer Destruction

Abstract

Teniposide (Ten/VM-26) is low in toxicity and has proven to be effective in destroying malignant cells at low doses. However, the target and molecular mechanism of Ten/VM-26 are poorly understood, which limits its clinical application against solid malignant cancers. Apurinic/apyrimidinic endonuclease 1 (APEX1) expression is upregulated in lung cancer, which could effectively suppress DNA damage. The present study aims to explore how Ten/VM-26 regulates APEX1 and thereby exploits its antilung cancer effects. Ten/VM-26 possessed powerful antilung cancer efficacy in vitro and organoid models. Furthermore, the findings of in vivo experiments evidenced that Ten/VM-26 could suppress the growth of tumor grafts without impacting the vital organs or body weight of mice. RNA-sequence analysis revealed that Ten/VM-26 treatment led to differentially expressed genes (DEGs), which were enriched in the DNA damage-associated biological process (BP). Reactive oxygen species (ROS) generation mediated by Ten/VM-26 was the major contributor to its anticancer effect. The in-depth investigation identified that APEX1 was efficiently expressed in lung cancer tissues, leading to a poor prognosis. Interestingly, APEX1 was downregulated in the presence of Ten/VM-26, which further abolished the protection of DNA, resulting in robust DNA damage. Further findings discovered that Ten/VM-26 could bind to APEX1 and thereby dampen its function. In contrast, APEX1 recovery attenuated the Ten/VM-26-induced DNA damage and anticancer efficacy. In summary, these data make a strong argument for the notion that Ten/VM-26-mediated inhibition of APEX1 contributes to DNA damage and thereby achieves favorable antilung cancer effects, wherein Ten/VM-26 could down-regulate APEX1 by binding and ubiquitination. The current study presents a critical target and mechanism for Ten/VM-26-mediated antilung cancer therapy.