Procaspase-Activating Compound-1 Synergizes with TRAIL to Induce Apoptosis in Established Granulosa Cell Tumor Cell Line (KGN) and Explanted Patient Granulosa Cell Tumor Cells In Vitro
Abstract
:1. Introduction
2. Results
2.1. Granulosa Cell Tumor Cells Display Sensitivity to PAC-1 and Other Select Apoptosis-Inducing Agents
2.2. PAC-1 Displays No or Low Synergy with Carboplatin, Gemcitabine or Embelin, But Strong Synergy with TRAIL in Killing KGN Cells
2.3. Using Mathematical Modelling to Validate Synergy of PAC-1 and TRAIL and Optimal Dosages
2.4. Combining TRAIL with PAC-1 Rapidly Induces Caspase-3 Activity in KGN Cells
2.5. Combining TRAIL with PAC-1 Reduces Proliferation and Increases Caspase-3 Activity in Patient-Derived Granulosa Cell Tumor Cells
3. Discussion
4. Materials and Methods
4.1. Cell Culture and Reagents
4.2. Cell Viability/Metabolism Assay
4.3. Caspase-3 Activity Assay (KGN Cells)
4.4. Patient-Derived GCT Cultures and Assays
4.5. Mathematical Model for Drug Induced KGN Cell Apoptosis
4.6. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AGCT | adult GCT |
ANOVA | one-way analysis of variance |
BID | BH3 interacting-domain death agonist |
DAPI | 4′,6-diamidino-2-phenylindole |
DMEM | Dulbecco’s modified Eagle’s medium |
DR | death receptor |
FBS | fetal bovine serum |
FITC | fluorescein isothiocyanate |
GCT | granulosa cell tumor |
IETD175 | Ile-Glu-Thr-Asp175 |
MTD | Maximum tolerated dose |
PAC-1 | procaspase-activating compound 1 |
PAGE | polyacrylamide gel electrophoresis |
PBS | phosphate-buffered saline |
RFU | relative fluorescence units |
RIPA | radio-immunoprecipitation assay |
SDS | sodium dodecyl sulfate |
shRNA | short hairpin RNA |
SMAC | second mitochondria-derived activator of caspase |
TRAIL | tumor necrosis factor-related apoptosis-inducing ligand |
XIAP | X-linked inhibitor of apoptosis |
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Drug | Residual a | Min Cell Viability b | |
---|---|---|---|
PAC-1 + Carboplatin | 1.6 | 0.0015 | 0.4 |
PAC1 + Embelin | 1.4 | 0.0073 | 0.16 |
PAC1 + Gemcitabine | 1.8 | 0.0055 | 0.32 |
PAC1 + TRAIL | 0.8 | 0.0050 | 0.14 |
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Crosley, P.; Farkkila, A.; Jenner, A.L.; Burlot, C.; Cardinal, O.; Potts, K.G.; Agopsowicz, K.; Pihlajoki, M.; Heikinheimo, M.; Craig, M.; et al. Procaspase-Activating Compound-1 Synergizes with TRAIL to Induce Apoptosis in Established Granulosa Cell Tumor Cell Line (KGN) and Explanted Patient Granulosa Cell Tumor Cells In Vitro. Int. J. Mol. Sci. 2021, 22, 4699. https://doi.org/10.3390/ijms22094699
Crosley P, Farkkila A, Jenner AL, Burlot C, Cardinal O, Potts KG, Agopsowicz K, Pihlajoki M, Heikinheimo M, Craig M, et al. Procaspase-Activating Compound-1 Synergizes with TRAIL to Induce Apoptosis in Established Granulosa Cell Tumor Cell Line (KGN) and Explanted Patient Granulosa Cell Tumor Cells In Vitro. International Journal of Molecular Sciences. 2021; 22(9):4699. https://doi.org/10.3390/ijms22094699
Chicago/Turabian StyleCrosley, Powel, Anniina Farkkila, Adrianne L. Jenner, Chloé Burlot, Olivia Cardinal, Kyle G. Potts, Kate Agopsowicz, Marjut Pihlajoki, Markku Heikinheimo, Morgan Craig, and et al. 2021. "Procaspase-Activating Compound-1 Synergizes with TRAIL to Induce Apoptosis in Established Granulosa Cell Tumor Cell Line (KGN) and Explanted Patient Granulosa Cell Tumor Cells In Vitro" International Journal of Molecular Sciences 22, no. 9: 4699. https://doi.org/10.3390/ijms22094699