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Mitochondria-derived reactive oxygen species drive GANT61-induced mesothelioma cell apoptosis
Chuan Bian Lim1, Cecilia M Prêle1,2, Svetlana Baltic1
1Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, School of Medicine and Pharmacology, University of Western Australia, Harry Perkins Institute of Medical Research, Nedlands, WA, Australia.
Abstract:
Gli transcription factors of the Hedgehog (Hh) pathway have been reported to be drivers of malignant mesothelioma (MMe) cell survival. The Gli inhibitor GANT61 induces apoptosis in various cancer cell models, and has been associated directly with Gli inhibition. However various chemotherapeutics can induce cell death through generation of reactive oxygen species (ROS) but whether ROS mediates GANT61-induced apoptosis is unknown. In this study human MMe cells were treated with GANT61 and the mechanisms regulating cell death investigated. Exposure of MMe cells to GANT61 led to G1 phase arrest and apoptosis, which involved ROS but not its purported targets, GLI1 or GLI2. GANT61 triggered ROS generation and quenching of ROS protected MMe cells from GANT61-induced apoptosis. Furthermore, we demonstrated that mitochondria are important in mediating GANT61 effects: (1) ROS production and apoptosis were blocked by mitochondrial inhibitor rotenone; (2) GANT61 promoted superoxide formation in mitochondria; and (3) mitochondrial DNA-deficient LO68 cells failed to induce superoxide, and were more resistant to apoptosis induced by GANT61 than wild-type cells. Our data demonstrate for the first time that GANT61 induces apoptosis by promoting mitochondrial superoxide generation independent of Gli inhibition, and highlights the therapeutic potential of mitochondrial ROS-mediated anticancer drugs in MMe.
Insights
The Gli inhibitor GANT61 triggers apoptosis in malignant mesothelioma cells by increasing mitochondrial reactive oxygen species (ROS), independent of Gli inhibition. This suggests a new therapeutic strategy targeting mitochondrial ROS for mesothelioma treatment.
Area of Science:
- Oncology
- Cell Biology
- Biochemistry
Background:
- Hedgehog (Hh) pathway transcription factors, particularly Gli, are implicated in malignant mesothelioma (MMe) cell survival.
- The Gli inhibitor GANT61 is known to induce apoptosis in cancer cells, but the underlying mechanisms, especially concerning reactive oxygen species (ROS), are not fully understood.
Purpose of the Study:
- To investigate the mechanisms of GANT61-induced cell death in human MMe cells.
- To determine if ROS mediates GANT61-induced apoptosis and to elucidate the role of mitochondria in this process.
Main Methods:
- Human MMe cells were treated with GANT61.
- Cell cycle arrest and apoptosis were assessed.
- ROS generation, particularly mitochondrial superoxide production, was measured.
- The effects of ROS quenching and mitochondrial inhibitors (rotenone) were evaluated.
- Mitochondrial DNA-deficient cells were used to assess mitochondrial involvement.
Main Results:
- GANT61 induced G1 phase arrest and apoptosis in MMe cells.
- GANT61 treatment led to increased ROS generation, and ROS quenching protected cells from apoptosis.
- Mitochondrial inhibition with rotenone blocked GANT61-induced ROS production and apoptosis.
- GANT61 promoted superoxide formation specifically in mitochondria.
- Mitochondrial DNA-deficient cells exhibited resistance to GANT61-induced apoptosis.
Conclusions:
- GANT61 induces apoptosis in malignant mesothelioma cells through the generation of mitochondrial superoxide, independent of Gli pathway inhibition.
- Mitochondrial ROS generation is a key mechanism mediating GANT61's anti-cancer effects in MMe.
- These findings highlight the potential of targeting mitochondrial ROS for mesothelioma therapy.
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