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Updated: May 21, 2025
Author Spotlight: Unveiling the Role of TMOD3 in Platinum Resistance and Immune Infiltration in Ovarian Cancer
Published on: August 2, 2024
Chemo-sensitive and chemo-resistant ovarian cancer cells show differences in cellular processes leading to pyroptotic
Caglar Berkel1, Aysun Keskin1, Ercan Cacan1
1Deparment of Molecular Biology and Genetics, Tokat Gaziosmanpasa University, Turkey.
Abstract:
Tumor immunology in ovarian cancer is not completely understood. Chemoresistance limits the success of available treatment options for patients with ovarian cancer. Pyroptosis, pro-inflammatory programmed cell death characterized by membrane pore formation by gasdermin proteins, is important for both immunogenicity and drug resistance. Here, we showed that estrogen increases GSDMC and GSDMD mRNA levels in chemo-sensitive ovarian cancer cells; but, not in chemo-resistant ovarian cancer cells in vitro. GSDMC or GSDMD overexpression increases cell viability in chemo-sensitive ovarian cancer cells; but, not in chemo-resistant ovarian cancer cells. Silencing of GSDMD in chemo-sensitive ovarian cancer cells and silencing of GSDMC in chemo-resistant ovarian cancer cells limit the effect of nigericin, a pyroptosis inducer, on cell viability. Inhibition of caspase-1, -4, -6 or -8 blocks nigericin-induced cell death (pyroptosis) in chemo-sensitive ovarian cancer cells; however, only the inhibition of caspase-1 blocks nigericin-induced cell death in chemo-resistant ovarian cancer cells, showing that caspases participating in pyroptosis might differ between ovarian cancer cells based on their chemo-sensitivity profiles. Treatment with disulfiram, a GSDMD pore formation inhibitor, decreases cell viability in both cell lines. Lastly, we found that in chemo-resistant ovarian cancer cell line, disulfiram and nigericin combination treatment decreases cell viability even more compared to only disulfiram or only nigericin treatment. Combined, our study points that ovarian cancer cells with different chemosensitivity profiles might have certain differences in pyroptotic cell death.
Insights
Pyroptosis, a programmed cell death, differs in ovarian cancer cells based on their chemo-sensitivity. Understanding these differences in pyroptosis mechanisms can inform new ovarian cancer treatments.
Area of Science:
- Oncology
- Cell Biology
- Immunology
Background:
- Ovarian cancer treatment is limited by chemoresistance.
- Pyroptosis, a programmed cell death pathway, influences immunogenicity and drug resistance.
Purpose of the Study:
- To investigate differences in pyroptosis mechanisms between chemo-sensitive and chemo-resistant ovarian cancer cells.
- To explore the role of gasdermin proteins and caspases in ovarian cancer pyroptosis.
Main Methods:
- Analyzing GSDMC and GSDMD mRNA levels in response to estrogen.
- Evaluating the impact of GSDMC/GSDMD overexpression and silencing on cell viability.
- Assessing pyroptosis induction by nigericin and its inhibition by caspase blockers.
- Testing the efficacy of disulfiram, a GSDMD inhibitor, alone and in combination with nigericin.
Main Results:
- Estrogen increased GSDMC/GSDMD mRNA in chemo-sensitive but not chemo-resistant cells.
- GSDMC/GSDMD overexpression affected cell viability differently based on chemo-sensitivity.
- Caspae involvement in nigericin-induced pyroptosis varied between cell lines.
- Disulfiram reduced cell viability in both cell types, with enhanced effect when combined with nigericin in chemo-resistant cells.
Conclusions:
- Ovarian cancer cells exhibit distinct pyroptotic cell death pathways depending on their chemo-sensitivity.
- Gasdermin proteins and caspases play differential roles in pyroptosis in ovarian cancer.
- Targeting pyroptosis pathways, potentially with drug combinations, may offer new therapeutic strategies for ovarian cancer.
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