The Selection of NFκB Inhibitors to Block Inflammation and Induce Sensitisation to FasL-Induced Apoptosis in HNSCC Cell Lines Is Critical for Their Use as a Prospective Cancer Therapy
Abstract
:1. Introduction
2. Results
2.1. HNSCC Cell Lines Secrete the Pro-Inflammatory Marker IL-8 and Are Responsive to TNFα
2.2. Inhibition of HNSCC Cell Proliferation by NFκB Inhibitors
2.3. Inhibition of the Inflammatory Response in HNSCC Cells by NFκB Inhibitors
2.4. TNFα Induced HNSCC Cell Death after TPCA1 Stimulation
2.5. Analysis of Extrinsic FasL-Induced Apoptosis in Combination with NFκB Inhibitors in HNSCC Cells
3. Discussion
4. Materials and Methods
4.1. Cell Culture
4.2. Crystal Violet Staining (CytoTox) Assay
4.3. ELISA
4.4. Statistical Analysis
Author Contributions
Funding
Conflicts of Interest
Abbreviations
BAFF | B-cell activating factor |
CCL-5 | CC-chemokine ligand 5 |
cFLIP | Cellular FLICE-like inhibitory protein |
CHX | Cycloheximide |
COX-2 | Cyclooxygenase-2 |
CV | Crystal violet |
HNSCC | Head and neck squamous cell carcinoma |
IAP | Inhibitor of apoptosis protein |
ICAM-1 | Intercellular adhesion molecule 1 |
IKK | IκB kinase |
IκB | Inhibitory κB |
IR | Ionising radiation |
KRAS | Kirsten rat sarcoma |
LTβ | Lymphotoxin-β |
MCP-1 | Monocyte chemoattractant protein 1 |
MMP | Matrix metalloproteinases |
NAE | NEDD8 activating enzyme |
NEDD8 | Neural precursor cell expressed developmentally down-regulated 8 |
NFκB | Nuclear factor kappa light-chain enhancer of activated B-cells |
NIK | NFκB-inducing kinase |
TNFα | Tumour necrosis factor α |
RANKL | Receptor activator of NFκB ligand |
RCN | Relative cell number |
VCAM-1 | Vascular cell adhesion protein 1 |
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Cortisol [µM] | MLN4924 [µM] | QNZ [µM] | TPCA1 [µM] | |||||
---|---|---|---|---|---|---|---|---|
IC10 | IC50 | IC10 | IC50 | IC10 | IC50 | IC10 | IC50 | |
PCI1 | 20 * | >280 ** | 0.2 | 1 | 0.05 | 1 | 4.6 | 9.7 |
PCI9 | 140 * | >280 ** | 3.1 * | >4.8 * | 1 † | >10 ** | 3.3 | 13.8 |
PCI13 | 140 * | >280 ** | 0.2 | 0.8 | 0.4 | 1.2 | 5.2 | 24.2 |
PCI52 | 140 * | >280 ** | 7.3* | >17.4 * | 1 † | >10 ** | 6.3 * | >17 * |
SCC25 | 140 * | >280 ** | 0.2 | 1.4 | 10 * | >10 ** | 3.5 | 6.1 |
HaCaT | 140 * | >280 ** | 0.2 | 0.8 | 0.4 | 1.1 | 2 | 5.3 |
PCI1 | PCI9 | PCI13 | PCI52 | SCC25 | HaCaT | |||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
RCN | ± | RCN | ± | RCN | ± | RCN | ± | RCN | ± | RCN | ± | |
Cortisol | 62 | 6.6 | 75.5 | 8.8 | 71.3 | 2.8 | 86.9 | 0.7 | 91 | 2.3 | 72.6 | 4.6 |
MLN4924 | 9.9 | 4.2 | 39.3 | 4.6 | 4.4 | 1.9 | 35.6 | 4.1 | 15.0 | 2.5 | 18.5 | 5.5 |
QNZ | 5.7 | 3.9 | 96.3 | 3.2 | 6.0 | 5.7 | 77.0 | 5.6 | 81.2 | 3.6 | 39.1 | 8.2 |
TPCA1 | 11.5 | 2.3 | 29.9 | 5.2 | 18.0 | 6.3 | 36.2 | 2.1 | 10.6 | 3.9 | 18.5 | 8.4 |
IC50 FasL [ng/mL] | Efficiency IC50 FasLmono/ IC50 FasLkombi) | Interaction Index (y) | |
---|---|---|---|
PCI1 | |||
FasL | 37.3 | - | - |
Cortisol [IC10] + FasL | >88.8 ± | 0.4 ± | 2.4 *** |
MLN4924 [IC10] + FasL | 33.6 | 1.1 | 1.1 *** |
QNZ [IC10] + FasL | 44.3 ± | 0.8 ± | 1.2 *** |
TPCA1 [IC10] + FasL | 41.9 ± | 0.9 ± | 1.6 *** |
PCI9 | |||
FasL | - † | - | - |
Cortisol [IC10] + FasL | >200 † | 1 | 1.5 *** |
MLN4924 [IC10] + FasL | >200 † | 1 | 1.7 *** |
QNZ [IC10] + FasL | >200 † | 1 | 1.1 *** |
TPCA1 [IC10] + FasL | >200 † | 1 | 1.2 *** |
PCI13 | |||
FasL | 55.5 | - | - |
Cortisol [IC10] + FasL | >200 ± | 0.3 ± | 4.1 *** |
MLN4924 [IC10] + FasL | >71.9 ± | 0.8 ± | 1.6 *** |
QNZ [IC10] + FasL | 24.4 | 2.3 | 0.8 * |
TPCA1 [IC10] + FasL | >55.1 ± | 1 | 1.2 *** |
PCI52 | |||
FasL | - † | - | - |
Cortisol [IC10] + FasL | >200 † | 1 | 1.5 *** |
MLN4924 [IC10] + FasL | >200 † | 1 | 1.4 *** |
QNZ [IC10] + FasL | >200 † | 1 | 1.1 *** |
TPCA1 [IC10] + FasL | >200 † | 1 | 1.4 *** |
SCC25 | |||
FasL | - † | - | - |
Cortisol [IC10] + FasL | >200 † | 1 | 1.5 *** |
MLN4924 [IC10] + FasL | 39.7 | 5 | 0.3 * |
QNZ [IC10] + FasL | >200 † | 1 | 2 *** |
TPCA1 [IC10] + FasL | >200 † | 1 | 1.6 *** |
HaCaT | |||
FasL | >68.7 ‡ | - | - |
Cortisol [IC10] + FasL | >59.1 | 1.2 | 1.4 *** |
MLN4924 [IC10] + FasL | 17.6 | 3.9 | 0.5 * |
QNZ [IC10] + FasL | 28.7 | 2.4 | 0.8 * |
TPCA1 [IC10] + FasL | 27.5 | 2.5 | 0.8 * |
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Scheurer, M.J.J.; Brands, R.C.; El-Mesery, M.; Hartmann, S.; Müller-Richter, U.D.A.; Kübler, A.C.; Seher, A. The Selection of NFκB Inhibitors to Block Inflammation and Induce Sensitisation to FasL-Induced Apoptosis in HNSCC Cell Lines Is Critical for Their Use as a Prospective Cancer Therapy. Int. J. Mol. Sci. 2019, 20, 1306. https://doi.org/10.3390/ijms20061306
Scheurer MJJ, Brands RC, El-Mesery M, Hartmann S, Müller-Richter UDA, Kübler AC, Seher A. The Selection of NFκB Inhibitors to Block Inflammation and Induce Sensitisation to FasL-Induced Apoptosis in HNSCC Cell Lines Is Critical for Their Use as a Prospective Cancer Therapy. International Journal of Molecular Sciences. 2019; 20(6):1306. https://doi.org/10.3390/ijms20061306
Chicago/Turabian StyleScheurer, Mario Joachim Johannes, Roman Camillus Brands, Mohamed El-Mesery, Stefan Hartmann, Urs Dietmar Achim Müller-Richter, Alexander Christian Kübler, and Axel Seher. 2019. "The Selection of NFκB Inhibitors to Block Inflammation and Induce Sensitisation to FasL-Induced Apoptosis in HNSCC Cell Lines Is Critical for Their Use as a Prospective Cancer Therapy" International Journal of Molecular Sciences 20, no. 6: 1306. https://doi.org/10.3390/ijms20061306