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Updated: Oct 21, 2025
Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
CXCL2-mediated ATR/CHK1 signaling pathway and platinum resistance in epithelial ovarian cancer
Sipei Nie1, Yicong Wan1, Hui Wang1
1Department of Gynecology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, Jiangsu, China.
Abstract:
Tumor microenvironment and chemokines play a significant role in cancer chemoresistance. This study was designed to reveal the important role of CXCL2 in platinum resistance in epithelial ovarian cancer (EOC). Differently expressed (DE) genes were screen out based on analysis of GSE114206 dataset in GEO database. The expression of DE chemokines was further validated in platinum- resistant and sensitive EOC. Cell viability assay and cell apoptosis assay were performed to explore the roles of CXCL2 in EOC. Cell stemness characteristics and the signaling pathway regulated by CXCL2 were also investigated in this study. As the results showed, CXCL2 was identified up-regulated in platinum-resistant EOC. The functional assays showed overexpressing CXCL2 or co-culturing with recombinant human CXCL2 promoted cell resistance to cisplatin. Conversely, knocking down CXCL2 or co-culturing with neutralizing antibody to CXCL2 increased cell response to cisplatin. CXCL2 overexpressing maintained cell stemness and activated ATR/CHK1 signaling pathway in EOC. Moreover, we further demonstrated that CXCL2-mediated resistance to cisplatin could be saved by SB225002, the inhibitor of CXCL2 receptor, as well as be rescued by SAR-020106, the inhibitor of ATR/CHK1 signaling pathway. This study identified a CXCL2-mediated mechanism in EOC platinum resistance. Our findings provided a novel target for chemoresistance prevention in EOC.
Insights
Chemokines like CXCL2 drive platinum resistance in epithelial ovarian cancer (EOC). Targeting CXCL2 and its pathways offers a new strategy to overcome chemoresistance in EOC patients.
Area of Science:
- Oncology
- Molecular Biology
- Immunology
Background:
- The tumor microenvironment and chemokines are critical factors in cancer treatment resistance.
- Understanding mechanisms of chemoresistance is vital for improving epithelial ovarian cancer (EOC) outcomes.
Purpose of the Study:
- To investigate the role of chemokine CXCL2 in platinum resistance in EOC.
- To elucidate the underlying molecular mechanisms of CXCL2-mediated chemoresistance.
Main Methods:
- Bioinformatic analysis of the GSE114206 dataset to identify differentially expressed genes.
- Validation of chemokine expression in platinum-resistant and sensitive EOC.
- In vitro functional assays including cell viability, apoptosis, and stemness assays.
- Investigation of the ATR/CHK1 signaling pathway and use of specific inhibitors (SB225002, SAR-020106).
Main Results:
- CXCL2 was significantly upregulated in platinum-resistant EOC.
- Overexpression of CXCL2 enhanced cisplatin resistance and promoted cell stemness.
- Knockdown of CXCL2 increased sensitivity to cisplatin.
- CXCL2 activated the ATR/CHK1 signaling pathway, contributing to chemoresistance.
- Inhibiting the CXCL2 receptor or ATR/CHK1 pathway reversed cisplatin resistance.
Conclusions:
- CXCL2 plays a significant role in mediating platinum resistance in EOC.
- The CXCL2/ATR/CHK1 signaling axis represents a novel therapeutic target for overcoming chemoresistance in EOC.
- Targeting CXCL2 could be a promising strategy for chemoresistance prevention in EOC.
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