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Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
RUNX3 contributes to carboplatin resistance in epithelial ovarian cancer cells
Samir H Barghout1, Nubia Zepeda2, Krista Vincent2
1Department of Obstetrics and Gynecology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.
Objective:
Resistance to platinum-based therapeutic agents represents a major hurdle in the treatment of epithelial ovarian cancer (EOC). There is an urgent need to better understand the underlying mechanisms. Here, we investigated the role of RUNX3 in carboplatin resistance in EOC cells.
Methods:
Expression of RUNX3 was determined in human EOC cell line A2780s (cisplatin-sensitive) and A2780cp (cisplatin-resistant), human ovarian surface epithelium (OSE) and primary EOC cells. The effects of RUNX3 expression on sensitivity to carboplatin were determined in A2780s and A2780cp cells using neutral red uptake and clonogenic assays. Carboplatin-induced apoptosis was determined by measuring cleaved PARP using Western blotting. The expression of cellular inhibitor of apoptosis protein-2 (cIAP2) and its regulation by RUNX3 were assessed by quantitative RT-PCR and Western blotting.
Results:
The expression of RUNX3 was elevated in A2780cp cells compared to A2780s cells and in EOC tissues from chemoresistant patients compared to those from chemosensitive patients. Overexpression of RUNX3 rendered A2780s cells more resistant to carboplatin, whereas inhibition of RUNX3 increased sensitivity to carboplatin in A2780cp cells. Inhibition of RUNX3 potentiated carboplatin-induced apoptosis in A2780cp cells as demonstrated by more pronounced PARP cleavage. Interestingly, the expression of cIAP2 was elevated in A2780cp cells compared to A2780s cells. Overexpression of RUNX3 increased cIAP2 expression in A2780s cells, whereas inhibition of RUNX3 decreased cIAP2 expression and potentiated carboplatin-induced decrease of cIAP2 in A2780cp cells.
Conclusions:
RUNX3 contributes to carboplatin resistance in EOC cells and may hold promise as a therapeutic target to treat EOC and/or a biomarker to predict chemoresistance.
Insights
RUNX3 promotes carboplatin resistance in epithelial ovarian cancer (EOC) by increasing cIAP2 expression. Targeting RUNX3 may overcome chemoresistance and serve as a biomarker for EOC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Platinum-based chemotherapy is a cornerstone treatment for epithelial ovarian cancer (EOC).
- Acquired resistance to platinum agents, such as carboplatin, significantly limits treatment efficacy in EOC.
- Understanding the molecular mechanisms driving carboplatin resistance is crucial for developing effective therapeutic strategies.
Purpose of the Study:
- To investigate the role of RUNX3 in the development of carboplatin resistance in EOC cells.
- To explore the potential of RUNX3 as a therapeutic target or predictive biomarker for EOC chemoresistance.
Main Methods:
- Assessed RUNX3 expression in cisplatin-sensitive and resistant EOC cell lines, ovarian surface epithelium, and primary EOC cells.
- Determined the impact of RUNX3 modulation on carboplatin sensitivity using cell viability and clonogenic assays.
- Evaluated carboplatin-induced apoptosis via Western blotting for cleaved PARP.
- Quantified cellular inhibitor of apoptosis protein-2 (cIAP2) expression and its regulation by RUNX3 using RT-PCR and Western blotting.
Main Results:
- RUNX3 expression was significantly higher in resistant EOC cells and tissues compared to sensitive counterparts.
- Overexpression of RUNX3 conferred carboplatin resistance, while RUNX3 inhibition enhanced sensitivity.
- RUNX3 inhibition potentiated carboplatin-induced apoptosis and reduced cIAP2 expression.
- RUNX3 positively regulated cIAP2 expression, contributing to chemoresistance.
Conclusions:
- RUNX3 plays a critical role in mediating carboplatin resistance in EOC.
- Targeting RUNX3 presents a promising strategy to overcome chemoresistance in EOC.
- RUNX3 may serve as a valuable biomarker for predicting chemoresistance in EOC patients.
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