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Arsenic trioxide induces autophagic cell death in osteosarcoma cells via the ROS-TFEB signaling pathway
Bowen Wu1, Miduo Tan2, Weiliang Cai3
1Department of Orthopedics and Trauma Surgery, Central Hospital of Zhuzhou City and Affiliated Zhuzhou Hospital of Xiangya Medical College of Central South University, Hunan, 412000, China.
Abstract:
Osteosarcoma is a common primary malignant bone tumor, the cure rate of which has stagnated over the past 25-30 years. Autophagy modulation has been considered a potential therapeutic strategy for osteosarcoma, and previous study indicated that arsenic trioxide (ATO) exhibits significant anti-carcinogenic activity. However, the ability of ATO to induce autophagy and its role in osteosarcoma cell death remains unclear. In the present study, we showed that ATO increased autophagic flux in the human osteosarcoma cell line MG-63, as evidenced by the upregulation of LC3-II and downregulation of P62/SQSTM1. Moreover, the pharmacological or genetic blocking autophagy decreased ATO -induced cell death, indicating that ATO triggered autophagic cell death in MG-63 cells. Mechanistically, ATO induced TFEB(Ser142) dephosphorylation, activated TFEB nuclear translocation and increased TFEB reporter activity, which contributed to lysosomal biogenesis and the expression of autophagy-related genes and subsequently initiated autophagic cell death in MG-63 cells. Importantly, ATO triggered the generation of ROS in MG-63 cells. Furthermore, NAC, an ROS scavenger, abrogated the effects of ATO on TFEB-dependent autophagic cell death. Taken together, these data demonstrate that ATO induces osteosarcoma cell death via inducing excessive autophagy, which is mediated through the ROS-TFEB pathway. The present study provides a new anti-tumor mechanism of ATO treatment in osteosarcoma.
Insights
Arsenic trioxide (ATO) triggers cancer cell death in osteosarcoma by inducing excessive autophagy through a reactive oxygen species (ROS)-TFEB pathway. Blocking autophagy inhibits ATO
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Osteosarcoma has a stagnant cure rate, necessitating novel therapeutic strategies.
- Autophagy modulation is a potential therapeutic avenue for osteosarcoma.
- Arsenic trioxide (ATO) shows anti-carcinogenic potential, but its role in osteosarcoma autophagy and cell death is unclear.
Purpose of the Study:
- To investigate the mechanism by which ATO induces cell death in osteosarcoma.
- To determine the role of autophagy in ATO-mediated osteosarcoma cell death.
- To elucidate the signaling pathway involved in ATO-induced autophagy.
Main Methods:
- Utilized the human osteosarcoma cell line MG-63.
- Assessed autophagic flux by monitoring LC3-II and P62/SQSTM1 levels.
- Investigated the role of autophagy using pharmacological and genetic inhibition.
- Examined TFEB phosphorylation, nuclear translocation, and reporter activity.
- Measured reactive oxygen species (ROS) generation and utilized N-acetylcysteine (NAC) as an ROS scavenger.
Main Results:
- ATO significantly increased autophagic flux in MG-63 cells.
- Inhibition of autophagy reduced ATO-induced cell death, confirming autophagic cell death.
- ATO induced TFEB dephosphorylation and nuclear translocation, promoting lysosomal biogenesis and autophagy-related gene expression.
- ATO triggered ROS generation, and ROS scavenging with NAC abrogated ATO's effects on TFEB-dependent autophagic cell death.
Conclusions:
- ATO induces osteosarcoma cell death by promoting excessive autophagy.
- The ROS-TFEB pathway mediates ATO-induced autophagic cell death in osteosarcoma.
- This study reveals a novel anti-tumor mechanism for ATO in osteosarcoma treatment.
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