Inhibition of Tyrosine-Phosphorylated STAT3 in Human Breast and Lung Cancer Cells by Manuka Honey is Mediated by Selective Antagonism of the IL-6 Receptor
Abstract
:1. Introduction
2. Results
2.1. MH-Induced Loss of p-STAT3 is Associated with Decreased gp130 and p-JAK2
2.2. Constitutive p-STAT3 is Dependent on Autocrine Activation
2.3. Exposure to MH Causes a Loss of p-STAT3, gp130, and p-JAK2 in A549 Lung Cancer Cells
2.4. MH Binds Competitively and Specifically to IL-6Rα
MH Flavonoids Bind to IL-6Rα
2.5. MH Flavonoids Exhibit Differential Inhibitory Capacity on STAT3 Phosphorylation
2.6. Docking Analysis Reveals Preferential Interaction Between Flavonoid Compounds and IL-6Ra
3. Discussion
4. Materials and Methods
4.1. Cell Line and Reagents
4.2. Western Blot Analysis
4.3. Enzyme-Linked Immunosorbent Assay
4.4. Competitive Cytokine Receptor Binding Assays
4.5. Docking Analysis
5. Statistical Analysis
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
MH | Manuka honey |
TNBC | Triple negative breast cancer |
NSCLC | Non-small cell lung cancer |
IL-6 | Interleukin-6 |
IL-6Rα | IL-6 receptor α chain |
IL-8R | IL-8 receptor |
IL-11Rα | IL-11 receptor α chain |
STAT3 | signal transducer and activator of transcription 3 |
p-STAT3 | tyrosine-phosphorylated STAT3 |
gp130 | Glycoprotein 130 |
JAK1/2 | Janus kinase 1/2 |
p-JAK2 | tyrosine-phosphorylated JAK2 |
SC | Sugar control |
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Flavonoid | Cluster | Estimated ∆G (kcal/mol) | Hydrogen Bonds |
---|---|---|---|
Luteolin (Lut) | 5 | −6.72 | Lut H7−−Pro7 O (1.851 Å) Lut H9−−Ala127 O (2.100 Å) Cys146 HN−−Lut O5 (2.341 Å) Cys174 SG−−Lut O3 (3.205 Å) |
Quercetin (Que) | 8 | −6.79 | Que H6−−Pro7 O (2.323 Å) Que H10−−Cys146 O (2.437 Å) Cys174 SG−−Que O3 (3.495 Å) |
Chrysin (Chr) | 6 | −6.42 | Chr H9−−Pro7 O (2.072 Å) Cys174 SG−−Chr O3 (3.307 Å) |
Pinocembrin (Pin) | 26 | −6.25 | Pin H11−−Lys126 O (2. 396 Å) Cys174SG−−Pin O3 (3.472Å) |
Galangin (Gal) | 14 | −6.83 | Gal H10−−Arg5 O (2.572 Å) Gal H8−−Glu10 OE2 (1.983 Å) Gln143 HE21−−Gal O1 (2.651 Å) |
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Aryappalli, P.; Shabbiri, K.; Masad, R.J.; Al-Marri, R.H.; Haneefa, S.M.; Mohamed, Y.A.; Arafat, K.; Attoub, S.; Cabral-Marques, O.; Ramadi, K.B.; et al. Inhibition of Tyrosine-Phosphorylated STAT3 in Human Breast and Lung Cancer Cells by Manuka Honey is Mediated by Selective Antagonism of the IL-6 Receptor. Int. J. Mol. Sci. 2019, 20, 4340. https://doi.org/10.3390/ijms20184340
Aryappalli P, Shabbiri K, Masad RJ, Al-Marri RH, Haneefa SM, Mohamed YA, Arafat K, Attoub S, Cabral-Marques O, Ramadi KB, et al. Inhibition of Tyrosine-Phosphorylated STAT3 in Human Breast and Lung Cancer Cells by Manuka Honey is Mediated by Selective Antagonism of the IL-6 Receptor. International Journal of Molecular Sciences. 2019; 20(18):4340. https://doi.org/10.3390/ijms20184340
Chicago/Turabian StyleAryappalli, Priyanka, Khadija Shabbiri, Razan J. Masad, Roadha H. Al-Marri, Shoja M. Haneefa, Yassir A. Mohamed, Kholoud Arafat, Samir Attoub, Otavio Cabral-Marques, Khalil B. Ramadi, and et al. 2019. "Inhibition of Tyrosine-Phosphorylated STAT3 in Human Breast and Lung Cancer Cells by Manuka Honey is Mediated by Selective Antagonism of the IL-6 Receptor" International Journal of Molecular Sciences 20, no. 18: 4340. https://doi.org/10.3390/ijms20184340