Fisetin Deters Cell Proliferation, Induces Apoptosis, Alleviates Oxidative Stress and Inflammation in Human Cancer Cells, HeLa
Abstract
:1. Introduction
2. Results
2.1. Fisetin Induces Morphological Changes and Inhibits Proliferation of HeLa Cells
2.2. Fisetin Changes Nuclear Morphology of HeLa Cells
2.3. Fisetin Leads DNA Fragmentation
2.4. Fisetin Encourages G2/M Arrest and Modulates Cell Cycle Regulatory Genes
2.5. Fisetin Shows Early Apoptosis on HeLa Cells
2.6. Fisetin Decreases TMRE Fluorescent Intensity
2.7. Fisetin Activates Extrinsic and Intrinsic Pathways
2.8. Fisetin Modulates Expression of Various Pro- and Anti-Apoptotic Proteins
2.9. Fisetin Elevates Caspase-3, Caspase-8 and Caspase-9 Activity
2.10. Fisetin Ameliorates Oxidation Stress in HeLa Cells by Upregulating GSH Activity
2.11. Fisetin Alleviates Inflammation in HeLa Cells
2.12. Fisetin Changes the Aberrant MAPK and PI3K/AKT/mTOR in HeLa Cells
3. Discussion
4. Materials and Methods
4.1. Cell lines and Reagents
4.2. Preparation of Drug Solutions
4.3. Cell Viability Assay
4.4. Nuclear Morphology by DAPI (4,6-diamidino-2-phenylindile) Staining
4.5. DNA Fragmentation Assay
4.6. Cell Cycle Analysis
4.7. Annexin V/Propidium Iodide Double Staining to Quantitate Apoptosis
4.8. TMRE Staining to Analyse Mitochondrial Membrane Potential
4.9. Gene Expression by TaqMan Apoptosis Array
4.10. Measurement of Apoptosis-Related Proteins Expression by Proteome Profiler Array
4.11. Phosphorylation Array
4.12. Caspases Multiplex Assay
4.13. Detection of GSH Activity in HeLa Cells
4.14. Inflammation Array
4.15. Statistical Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
TNF | Tumour necrotic factor |
FASL | Fas ligand |
TRAIL | Tumour necrosis factor-related apoptosis-inducing ligand |
PARP | Poly [ADP ribose] polymerase 1 |
PI | propidium iodide |
PI3KCD | phosphotidyl-inositol-4,5-bisphosphate 3-kinase catalytic subunit delta |
PTPRR | protein tyrosine phosphatase receptor type R |
qPCR | quantitative real time polymerase chain reaction |
TERT | telomerase reverse transcriptase |
IL | Interleukin |
MAPK | Mitogen activated protein kinase |
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Hall Mark | Molecular Target | Transcript Expression | Protein Expression | ||
---|---|---|---|---|---|
Upregulation | Downregulation | Upregulation | Downregulation | ||
Apoptosis | Caspases | CASP9, CASP7, CASP3, CASP6, CASP4, CASP8AP2, CASP2, CASP1 and CASP8 | Caspase-3 and Caspase-8 | ||
Pro-apoptotic gene | APAF-1, BCL10, BCL2A1, BCL2L1, BCL2L13, BCL2L2, BAD, BAK1 and BAX, BOK, HTRA2, PYCARD, RIPK1, RIPK2, BID, PYCARD, RIPK2 and RIPK1. | Bad, Bax, Bid, Bim, P21, p53, p27, (ligand), cyt-c and HSP27. | |||
Death receptors | FAS, FASL, CARD6, CARD9, CRADD, DEDD, FADD, TNF, TNFRSFS10A and TNFRSFS10B | Fas, Fas ligand, TNFRII, TNFα, TNF β, TNFRF, TNFSFS, TRAIL R1 to TRAIL R4. | |||
Anti-apoptotic gene | BCL2, MCL1, BIRC5, and NAIP | Bcl-2, BCL-w, clap-2, HSP70, LIVIN, Survivin and XIAP. | |||
Sustained cell proliferation | Cell cycle regulation | CCNB1, CCNB2, CCNE2, CDKN2A and CDK4. | |||
Anti-proliferation and TSGs (Tumour suppressor genes) | PTPRR, FOXO 1, FOXO 3. ATM, ATF2 and TP53 | TERT | |||
Inflammation and anti-oxidation | IL-2 and MYC, | IL-10 and IL-13 | IL-1α, IL-1β, IL-4, IL-7, IL-11 IL-16, IL-12p70, MIG, MCP-1, MCP-2, MIP-1β, MIP-1γ, MCF, I-309 and EOTAXIN |
Hall Mark | Molecular Target | Transcript Expression | Protein Expression | ||
---|---|---|---|---|---|
Upregulation | Downregulation | Upregulation | Downregulation | ||
Pathways:Anti-proliferation, anti-inflammation and apoptosis-inducing pathway | MAPK | MAPK1, MAK14, MAP2K1, MAP2K6, ELK 1 | p38 (P-Thr180/Tyr182) and P53 (P-Ser15) | RSK1 (P-Ser380) and Raf-1 (P-Ser301) | |
AKT/MTPR/PI3K | AKT2, MTOR, PIK3C2B, PIK3CB. | p27 (P-Thr198) | GSK3a (p-ser21), GSK3b (p-ser9), MTOR (p-ser2448), PRAS 40 (p-Ther246), BAD (p-ser112), PTEN (p-ser380), AKT (p-ser473), AMPKa (P-Thr172), RPS6 (P-Ser235/236), and 4E-BP1 (P-Thr36). | ||
JAK-STAT and NF-kB | Src (P-Tyr419), STAT1 (P-Ser727), STAT2 (P-Tyr689), STAT3 (P-Tyr705), STAT5 (P-Tyr694), TYK2 (P-Tyr1054), HDAC4 (P-Ser632), NF-kB (P-Ser536), TAK1 (P-Ser412) and TBK1 (P-Ser172). |
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Afroze, N.; Pramodh, S.; Shafarin, J.; Bajbouj, K.; Hamad, M.; Sundaram, M.K.; Haque, S.; Hussain, A. Fisetin Deters Cell Proliferation, Induces Apoptosis, Alleviates Oxidative Stress and Inflammation in Human Cancer Cells, HeLa. Int. J. Mol. Sci. 2022, 23, 1707. https://doi.org/10.3390/ijms23031707
Afroze N, Pramodh S, Shafarin J, Bajbouj K, Hamad M, Sundaram MK, Haque S, Hussain A. Fisetin Deters Cell Proliferation, Induces Apoptosis, Alleviates Oxidative Stress and Inflammation in Human Cancer Cells, HeLa. International Journal of Molecular Sciences. 2022; 23(3):1707. https://doi.org/10.3390/ijms23031707
Chicago/Turabian StyleAfroze, Nazia, Sreepoorna Pramodh, Jasmin Shafarin, Khuloud Bajbouj, Mawieh Hamad, Madhumitha Kedhari Sundaram, Shafiul Haque, and Arif Hussain. 2022. "Fisetin Deters Cell Proliferation, Induces Apoptosis, Alleviates Oxidative Stress and Inflammation in Human Cancer Cells, HeLa" International Journal of Molecular Sciences 23, no. 3: 1707. https://doi.org/10.3390/ijms23031707