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Proteomics discovery of MTDH and SND1 interaction vulnerabilities in ovarian cancer
Parisa Esmaeili1, Ahmad Nasimian2, Lucas Werner1
1Department of Immunotechnology, Lund University, Lund, 223 81, Sweden.
Abstract:
High-grade serous ovarian cancer (HGSOC) is the most prevalent and aggressive subtype of ovarian cancer. The combination of late-stage diagnosis and the tendency to exhibit resistance to existing treatments highlights a critical gap in effective therapeutic options. There is thus a need for novel strategies for targeting HGSOC, particularly in its advanced stages. To address this gap, we developed a comprehensive atlas profiling both the proteome and phosphoproteome levels across a panel of nine ovarian cancer cell lines from different subtypes. Subsequent differential expression analysis between the KURAMOCHI and the other cell lines, followed by phosphosite analyses, proposed the MTDH protein as a potential target. Further functional analyses of MTDH and the interacting protein SND1 with RNA silencing, as well as targeting their interaction, revealed that disrupting this interaction leads to the dysregulation of several pathways associated with cancer progression and invasion. In particular, interference with the MTDH-SND1 complex was associated with enrichment of ferroptosis-related pathways. Moreover, combining C26A6 treatment with ferroptosis inducers produced enhanced inhibitory effects in ovarian cancer cells, suggesting a possible strategy for targeting cancer cell vulnerabilities in HGSOC, which warrants further investigation beyond in vitro models.
Insights
Researchers identified the MTDH-SND1 protein complex as a potential therapeutic target for high-grade serous ovarian cancer (HGSOC). Disrupting this complex enhances ferroptosis, offering a novel strategy against this aggressive cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- High-grade serous ovarian cancer (HGSOC) is aggressive, often diagnosed late, and resistant to treatments.
- Existing therapies for advanced HGSOC are limited, necessitating novel therapeutic strategies.
- Comprehensive proteomic and phosphoproteomic profiling is crucial for identifying new drug targets.
Purpose of the Study:
- To identify novel therapeutic targets for high-grade serous ovarian cancer (HGSOC).
- To investigate the role of the MTDH-SND1 protein complex in HGSOC progression.
- To explore the potential of targeting the MTDH-SND1 interaction and ferroptosis pathways.
Main Methods:
- Proteomic and phosphoproteomic analysis of nine ovarian cancer cell lines.
- Differential expression analysis to identify key proteins.
- RNA silencing and functional assays to study protein interactions and pathway dysregulation.
- Combination therapy studies involving C26A6 and ferroptosis inducers.
Main Results:
- The MTDH protein was identified as a potential therapeutic target.
- Disruption of the MTDH-SND1 interaction led to dysregulation of cancer progression and invasion pathways.
- Interference with the MTDH-SND1 complex enriched ferroptosis-related pathways.
- Combined treatment with C26A6 and ferroptosis inducers showed enhanced inhibitory effects on ovarian cancer cells.
Conclusions:
- The MTDH-SND1 complex is a promising target for HGSOC therapy.
- Targeting the MTDH-SND1 interaction can induce ferroptosis and inhibit cancer progression.
- Combination therapy involving ferroptosis inducers presents a potential strategy for treating HGSOC.
