Asparagine Synthetase and Filamin A Have Different Roles in Ovarian Cancer

Area of Science:

• Proteomics and molecular oncology.
• Biomarker discovery for gynecological cancers.

Background:

• Early-stage ovarian serous carcinoma detection is challenging.
• Understanding protein expression differences in high-grade (HGSC) and low-grade (LGSC) serous carcinoma is crucial for diagnosis and chemotherapy selection.

Purpose of the Study:

• To profile protein expression in HGSC and LGSC.
• To identify potential protein biomarkers for distinguishing HGSC and LGSC.
• To investigate the role of identified proteins in cisplatin sensitivity and resistance.

Main Methods:

• Proteomic profiling using iTRAQ on patient specimens (13 HGSC, 7 LGSC).
• Immunohistochemical validation of differentially expressed proteins in 166 clinical tissues.
• Functional studies using engineered ovarian cancer cell lines (SKOV3, OVCAR3) and *in vivo* xenograft models to assess the impact of asparagine synthetase (ASNS) and filamin A (FLNA) on cisplatin response.

Main Results:

• Identified 323 differentially expressed proteins; ASNS and FLNA were selected for further study.
• ASNS overexpression or FLNA knockdown sensitized cisplatin-resistant cells to apoptosis and autophagy, but differentially affected tumor growth.
• ASNS knockdown or FLNA overexpression modulated cisplatin sensitivity in cisplatin-sensitive cells.
• ASNS and FLNA expression correlated with cisplatin response in *in vivo* models and clinical outcomes, with HGSC patients showing universal response and LGSC patients exhibiting some resistance.

Conclusions:

• ASNS and FLNA are distinct biomarkers capable of differentiating HGSC from LGSC.
• These proteins may serve as valuable prognostic indicators and therapeutic targets for serous ovarian carcinoma.
• Targeting ASNS and FLNA could offer novel strategies for overcoming cisplatin resistance in ovarian cancer.