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Breaking the cancer code: a novel DNA minicircle to disable STAT3 in ovarian cancer cells SKOV3
Adina-Gabriela Vasilescu1, Andrei-Mihai Vasilescu1, Livia Elena Sima2
1Department of Enzymology, Institute of Biochemistry of the Romanian Academy, Bucharest, Romania.
Introduction:
Ovarian Cancer remains a significant global health concern, with high mortality rates, largely due to late-stage diagnosis and limited treatment options. These extrinsic factors are driven or exacerbated by intrinsic mechanisms such as persistent activation or upregulation of Signal Transducer and Activator of Transcription 3 (STAT3). STAT3 promotes tumor growth, inhibits apoptosis, accelerates angiogenesis and metastasis, facilitates immune evasion, and contributes to chemoresistance. Consequently, STAT3 activation fosters an aggressive ovarian cancer phenotype, contributing to treatment failure, poor prognosis and low survival rates, highlighting the urgent need for novel, safe, effective and affordable STAT3-targeted therapeutic strategies. In this study, we developed a novel double-stranded DNA minicircle (mcDNA) inhibitor, designed to act as a decoy for STAT3, preventing its binding to target gene promoters.
Methods:
Utilizing the SKOV3 ovarian cancer cell line, we evaluated the effects of our inhibitor in vitro on cell viability through MTS assay, its apoptotic and necrotic effects using flow cytometry and the expression modulation of downstream STAT3-regulated genes, assayed through RT-qPCR and Western blot analysis.
Results:
We demonstrate that anti-STAT3 mcDNA significantly reduces the viability of SKOV3 cells at low nanomolar concentrations, while sparing the control group. The effect observed was dose-dependent. Mechanistically, anti-STAT3 mcDNA induces apoptosis and necrosis in treated cells, also revealing a certain dose-dependency, while also decreasing cell proliferation. Finally, our inhibitor significantly downregulates STAT3-dependent anti-apoptotic genes MCL1 and PIM1.
Conclusion:
These findings suggest that anti-STAT3 mcDNA is a promising, effective and specific candidate for targeted STAT3 inhibition in SKOV3 ovarian cancer cells, warranting further validation in ovarian cancer, in vivo exploration and potential application in other types of malignancies, where STAT3 acts as an oncogenic factor.
Insights
A novel DNA minicircle inhibitor targeting Signal Transducer and Activator of Transcription 3 (STAT3) effectively reduced ovarian cancer cell viability and proliferation. This STAT3 inhibitor shows promise for treating ovarian cancer by downregulating key oncogenic genes.
Area of Science:
- Oncology
- Molecular Biology
- Gene Therapy
Background:
- Ovarian cancer presents a significant global health challenge with high mortality, often linked to late diagnosis and limited treatment efficacy.
- Persistent activation of Signal Transducer and Activator of Transcription 3 (STAT3) is a key intrinsic mechanism driving tumor growth, metastasis, immune evasion, and chemoresistance in ovarian cancer.
- The aggressive phenotype fostered by STAT3 contributes to treatment failure and poor patient survival, underscoring the need for targeted STAT3 therapies.
Purpose of the Study:
- To develop and evaluate a novel double-stranded DNA minicircle (mcDNA) inhibitor designed to act as a decoy for STAT3, thereby preventing its binding to target gene promoters.
- To assess the efficacy of the anti-STAT3 mcDNA inhibitor in reducing ovarian cancer cell viability, inducing apoptosis and necrosis, and modulating STAT3-regulated gene expression in vitro.
Main Methods:
- The study utilized the SKOV3 ovarian cancer cell line for in vitro experiments.
- Cell viability was assessed using the MTS assay.
- Apoptotic and necrotic effects were evaluated via flow cytometry, and the expression of STAT3-regulated genes was analyzed using RT-qPCR and Western blot analysis.
Main Results:
- The anti-STAT3 mcDNA inhibitor significantly reduced SKOV3 cell viability at low nanomolar concentrations in a dose-dependent manner.
- Treatment with anti-STAT3 mcDNA induced apoptosis and necrosis in treated cells and decreased cell proliferation.
- The inhibitor effectively downregulated STAT3-dependent anti-apoptotic genes, specifically MCL1 and PIM1.
Conclusions:
- The developed anti-STAT3 mcDNA demonstrates significant potential as an effective and specific inhibitor of STAT3 in ovarian cancer cells.
- These findings support further validation of anti-STAT3 mcDNA in ovarian cancer models, including in vivo studies.
- The therapeutic strategy may also be applicable to other malignancies where STAT3 plays a critical oncogenic role.
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