Mitochondrial outer membrane protein MTUS1/ATIP1 exerts antitumor effects through ROS-induced mitochondrial
Dongxiao Tang1,2, Luodan Zhao3, Shuojin Huang1
1Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China.
Abstract:
We showed that microtubule-associated tumor suppressor gene (MTUS1/ATIP) downregulation correlated with poor survival in head and neck squamous cell carcinoma (HNSCC) patients and that MTUS1/ATIP1 was the most abundant isoform in HNSCC tissue. However, the location and function of MTUS1/ATIP1 have remain unclear. In this study, we confirmed that MTUS1/ATIP1 inhibited proliferation, growth and metastasis in HNSCC in cell- and patient-derived xenograft models in vitro and in vivo. MTUS1/ATIP1 localized in the outer mitochondrial membrane, influence the morphology, movement and metabolism of mitochondria and stimulated oxidative stress in HNSCC cells by directly interacting with MFN2. MTUS1/ATIP1 activated ROS, recruiting Bax to mitochondria, facilitating cytochrome c release to the cytosol to activate caspase-3, and inducing GSDME-dependent pyroptotic death in HNSCC cells. Our findings showed that MTUS1/ATIP1 localized in the outer mitochondrial membrane in HNSCC cells and mediated anticancer effects through ROS-induced pyroptosis, which may provide a novel therapeutic strategy for HNSCC treatment.
Insights
Microtubule-associated tumor suppressor gene 1 (MTUS1/ATIP1) inhibits head and neck cancer growth and metastasis. This protein triggers cell death via oxidative stress and pyroptosis, offering a potential new treatment strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Downregulation of microtubule-associated tumor suppressor gene (MTUS1/ATIP) correlates with poor survival in head and neck squamous cell carcinoma (HNSCC).
- The precise location and function of the MTUS1/ATIP1 isoform in HNSCC remain largely uncharacterized.
Purpose of the Study:
- To elucidate the subcellular localization and functional role of MTUS1/ATIP1 in HNSCC.
- To investigate the mechanism by which MTUS1/ATIP1 exerts its tumor-suppressive effects in HNSCC.
Main Methods:
- In vitro and in vivo studies using cell- and patient-derived xenograft models of HNSCC.
- Mitochondrial localization studies, interaction analysis with MFN2, assessment of oxidative stress (ROS) and apoptosis/pyroptosis pathways (Bax, cytochrome c, caspase-3, GSDME).
Main Results:
- MTUS1/ATIP1 was confirmed to inhibit proliferation, growth, and metastasis in HNSCC models.
- MTUS1/ATIP1 localizes to the outer mitochondrial membrane, influencing mitochondrial morphology, dynamics, and metabolism.
- MTUS1/ATIP1 directly interacts with MFN2, stimulating ROS production, promoting Bax recruitment to mitochondria, facilitating cytochrome c release, and inducing GSDME-dependent pyroptosis.
Conclusions:
- MTUS1/ATIP1 acts as a tumor suppressor in HNSCC by localizing to the outer mitochondrial membrane.
- MTUS1/ATIP1 mediates anticancer effects through ROS-induced pyroptosis, highlighting its potential as a novel therapeutic target for HNSCC.
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