Molecular Mechanisms of Antiproliferative and Apoptosis Activity by 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)1,4-Pentadiene-3-one (MS13) on Human Non-Small Cell Lung Cancer Cells
Abstract
:1. Introduction
2. Results
2.1. Cytotoxic Effects of MS13 on NCI-H520 and NCI-H23 Cell Lines
2.2. Antiproliferative Effect of MS13 on NCI-H520 and NCI-H23 Cell Lines
2.3. Morphological Observation of Apoptotic Cells by Acridine Orange
2.3.1. Propidium Iodide (AO-PI) Double Staining
2.3.2. Quantification of Apoptotic and Necrotic Cells
2.3.3. Quantification of Relative Caspase-3 Activity
2.3.4. Quantification of Bcl-2 Protein Concentration
2.4. Analysis of Differentially Expressed Genes (DEGs) in MS13-Treated Lung Cancer Cells Associated with PI3K-AKT, Cell Cycle-Apoptosis, and MAPK Pathways
3. Discussion
4. Materials and Methods
4.1. Cell Culture and Maintenance
4.2. Preparation of Curcumin Analogue (MS13) and Curcumin
4.3. Cell Viability and Antiproliferative Assays
4.4. Induction of Apoptosis by MS13
4.4.1. Morphological Evaluation of Apoptotic Cells by Acridine Orange–Propidium Iodide (AO-PI) Double Staining
- viable cells exhibit uniform green nuclei with intact structure
- early apoptotic cells exhibit bright-green to yellow nuclei. In addition, characteristics of membrane integrity loss and chromatin condensation
- late apoptotic cells exhibit yellow-orange to bright red nuclei as well as condensed or fragmented chromatin,
- necrotic cells exhibit bright orange or red uniform nuclei.
4.4.2. Caspase-3 Activity
4.4.3. Bcl-2 Cellular Protein Concentration
4.5. Gene Expression Analysis
4.5.1. Total mRNA Extraction
4.5.2. Nanostring nCounter Gene Expression Analysis
4.5.3. Sample Loading Protocol for nCounter SPRINTTM Profiler
4.5.4. Data Collection and Data Analysis
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Compounds | EC50 Values (µM) | Selective Index (SX) | |||
---|---|---|---|---|---|
NCI-H520 | NCI-H23 | MRC9 | NCI-H520 | NCI-H23 | |
MS13 | 4.7 ± 0.1 | 3.7 ± 0.4 | 8.6 ± 0.6 | 181.4 | 232.4 |
Curcumin | 25.19 ± 1.7 | 18.5 ± 0.7 | 27.4 ± 1.7 | 108.8 | 148.2 |
Genes/Cell Line | Gene Description | Accession No. | Single/Multiple Pathways | FC | p-Value |
---|---|---|---|---|---|
NCI-H520 | |||||
PTEN | Phosphatase and Tensin Homolog | NM_000314.3:1675 | PI3K | 1.3 | 0.0233 |
DDIT4 | DNA Damage Inducible Transcript 4 | NM_019058.2:85 | PI3K | 1.4 | 0.0223 |
ENDOG | Endonuclease G | NM_004435.2:694 | Cell-cycle Apoptosis | 1.5 | 0.00367 |
CASP8 | Caspase 8 | NM_001228.4:301 | Cell-cycle Apoptosis | 1.4 | 0.0341 |
DDIT3 | DNA Damage Inducible Transcript 3 | NM_004083.4:40 | MAPK | 1.3 | 0.00325 |
CDKN1A | Cyclin Dependent Kinase Inhibitor 1A | NM_000389.2:1975 | Cell-cycle Apoptosis and PI3K | 2.1 | 0.0006 |
* CCND3 | Cyclin D3 | NM_001760.2:1215 | Cell-cycle Apoptosis and PI3K | 1.4 | 0.015 |
GADD45G | Growth Arrest and DNA Damage Inducible Gamma | NM_006705.3:250 | Cell-cycle Apoptosis and MAPK | 2.1 | 0.000258 |
NCI-H23 | |||||
ITGA2 | Integrin Subunit Alpha 2 | NM_002203.2:475 | PI3K | 1.4 | 0.00405 |
THEM4 | Thioesterase Superfamily Member 4 | NM_053055.4:764 | PI3K | 1.3 | 0.00716 |
TNFRSF10A | TNF Receptor Superfamily Member 10a | NM_003840.3:2380 | Cell-cycle Apoptosis | 1.4 | 0.00918 |
IRAK2 | Interleukin 1 Receptor Associated Kinase 2 | NM_001570.3:1285 | Cell-cycle Apoptosis | 1.4 | 0.00186 |
DUSP2 | Dual Specificity Phosphatase 2 | NM_004418.3:1235 | MAPK | 1.3 | 0.0344 |
* CCND3 | Cyclin D3 | NM_001760.2:1215 | Cell-cycle Apoptosis and PI3K | 1.3 | 0.00733 |
Genes/Cell Line | Gene Description | Accession No. | Single/Multiple Pathways | FC | p-Value |
---|---|---|---|---|---|
NCI-H520 | |||||
EPHA2 | EPH Receptor A2 | NM_004431.2:1525 | PI3K | −2.0 | 0.00397 |
NGFR | Nerve Growth Factor Receptor | NM_002507.1:2705 | PI3K | −2.0 | 0.00691 |
MYB | MYB Proto-Oncogene, Transcription Factor | NM_005375.2:3145 | PI3K | −1.9 | 0.00042 |
ITGB4 | Integrin Subunit Beta 4 | NM_001005731.1:4151 | PI3K | −1.7 | 0.00064 |
COL4A5 | Collagen Type IV Alpha 5 Chain | NM_033381.1:5360 | PI3K | −1.7 | 0.00275 |
* THBS1 | Thrombospondin 1 | NM_003246.2:3465 | PI3K | −1.7 | 0.00044 |
KIT | KIT Proto-Oncogene, Receptor Tyrosine Kinase | NM_000222.1:5 | PI3K | −1.6 | 0.0418 |
KITLG | KIT Ligand | NM_003994.4:1155 | PI3K | −1.5 | 0.00058 |
PDGFD | Platelet Derived Growth Factor D | NM_025208.4:1120 | PI3K | −1.4 | 0.0496 |
FN1 | Fibronectin 1 | NM_212482.1:1776 | PI3K | −1.3 | 0.00927 |
ITGA2 | Integrin Subunit Alpha 2 | NM_002203.2:475 | PI3K | −1.3 | 0.0199 |
* MCM-7 | Minichromosome Maintenance Complex Component 7 | NM_182776.1:1325 | Cell-cycle Apoptosis | −4.3 | 1.62 × 10−5 |
E2F1 | E2F Transcription Factor 1 | NM_005225.1:935 | Cell-cycle Apoptosis | −1.5 | 0.00051 |
MAP2K1 | Mitogen-Activated Protein Kinase Kinase 1 | NM_002755.2:970 | Cell-cycle Apoptosis | −1.4 | 0.00012 |
CDKN2C | Cyclin Dependent Kinase Inhibitor 2C | NM_001262.2:1295 | Cell-cycle Apoptosis | −1.4 | 0.013 |
PRKAR1B | Protein Kinase CAMP-Dependent Type I Regulatory Subunit Beta | NM_001164759.1:1112 | Cell-cycle Apoptosis | −1.4 | 0.00524 |
CDKN2D | Cyclin-Dependent Kinase Inhibitor 2D | NM_001800.3:870 | Cell-cycle Apoptosis | −1.4 | 0.0333 |
CASP7 | Caspase 7 | NM_001227.3:915 | Cell-cycle Apoptosis | −1.3 | 0.0198 |
PKMYT1 | Protein Kinase, Membrane-Associated Tyrosine/Threonine 1 | NM_004203.3:780 | Cell-cycle Apoptosis | −1.3 | 0.00813 |
HDAC10 | Histone Deacetylase 1 | NM_032019.5:932 | Cell-cycle Apoptosis | −1.3 | 0.00159 |
MYD88 | Innate Immune Signal Transduction Adaptor | NM_002468.3:2145 | Cell-cycle Apoptosis | −1.3 | 0.00872 |
* SKP2 | S-Phase Kinase-Associated Protein 2 | NM_005983.2:615 | Cell-cycle Apoptosis | −1.3 | 0.00401 |
CACNA2D2 | Calcium Voltage-Gated Channel Auxiliary Subunit Alpha2delta 2 | NM_001005505.1:2045 | MAPK | −2.1 | 0.0113 |
CACNA1E | Calcium Voltage-Gated Channel Subunit Alpha1 E | NM_000721.2:9325 | MAPK | −2.1 | 0.00435 |
DUSP4 | Dual Specificity Phosphatase 4 | NM_057158.2:3115 | MAPK | −1.6 | 0.0319 |
MAP2K6 | Mitogen-Activated Protein Kinase Kinase 6 | NM_002758.3:555 | MAPK | −1.5 | 0.00795 |
* MAPT | Microtubule Associated Protein Tau | NM_016834.3:1205 | MAPK | −1.5 | 0.0469 |
THSBP1 | Heat Shock Factor Binding Protein 1 | NM_003246.2:3465 | MAPK | −1.5 | 0.0123 |
DUSP6 | Dual Specificity Phosphatase 6 | NM_001946.2:1535 | MAPK | −3.3 | 6.93 × 10−5 |
RASGRP1 | RAS Guanyl Releasing Protein 1 | NM_005739.3:365 | MAPK | −1.7 | 0.0297 |
PIK3R2 | Phosphoinositide-3-Kinase Regulatory Subunit 2 | NM_005027.2:3100 | Cell cycle-apoptosis and PI3K | −1.5 | 0.00943 |
BAD | BCL2 Associated Agonist of Cell Death | NM_004322.3:652 | Cell cycle-apoptosis and PI3K | −1.4 | 0.00012 |
CDK6 | Cyclin-Dependent Kinase 6 | NM_001259.5:15 | Cell cycle-apoptosis and PI3K | −1.4 | 0.00398 |
PIK3R3 | Phosphoinositide-3-Kinase Regulatory Subunit 3 | NM_003629.3:1800 | Cell cycle-apoptosis and PI3K | −1.3 | 0.00023 |
* PIK3CB | Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Beta | NM_006219.1:2945 | Cell cycle-apoptosis and PI3K | −1.3 | 0.00023 |
FGF9 | Fibroblast Growth Factor 9 | NM_002010.2:1565 | PI3K and MAPK | −1.8 | 0.00742 |
PRKCA | Protein Kinase C Alpha | NM_002737.2:5560 | PI3K and MAPK | −1.6 | 0.0235 |
MAP2K1 | Mitogen-Activated Protein Kinase Kinase 1 | NM_002755.2:970 | PI3K and MAPK | −1.4 | 0.000117 |
MAP2K2 | Mitogen-Activated Protein Kinase Kinase 2 | NM_030662.2:1325 | PI3K and MAPK | −1.4 | 0.00258 |
* MAPK3 | Mitogen-Activated Protein Kinase 3 | NM_001040056.1:580 | PI3K and MAPK | −1.3 | 0.016 |
* TGFB2 | Transforming Growth Factor Beta 2 | NM_003238.2:1125 | Cell cycle-apoptosis and MAPK | −1.5 | 0.00123 |
PRKACA | Protein Kinase CAMP-Activated Catalytic Subunit Alpha | NM_002730.3:400 | Cell cycle-apoptosis, PI3K and MAPK | −1.3 | 4.50 × 10−5 |
AKT1 | AKT Serine/Threonine Kinase 1 | NM_005163.2:1772 | Cell cycle-apoptosis, PI3K and MAPK | −1.3 | 0.0007 |
NCI-H23 | |||||
HGF | Hepatocyte Growth Factor | NM_000601.4:550 | PI3K | −1.8 | 0.0285 |
COL5A2 | Collagen Type V Alpha 2 Chain | NM_000393.3:4075 | PI3K | −1.7 | 0.00464 |
GNG4 | G Protein Subunit Gamma 4 | NM_004485.2:215 | PI3K | −1.6 | 0.028 |
MET | MET Proto-Oncogene, Receptor Tyrosine Kinase | NM_000245.2:405 | PI3K | −1.5 | 0.00293 |
ITGA3 | Integrin Subunit Alpha 3 | NM_005501.2:1138 | PI3K | −1.5 | 0.0131 |
* THBS1 | Thrombospondin 1 | NM_003246.2:3465 | PI3K | −1.4 | 0.00578 |
IRS1 | Insulin Receptor Substrate 1 | NM_005544.2:6224 | PI3K | −1.4 | 0.00412 |
EFNA3 | Ephrin A3 | NM_004952.4:1672 | PI3K | −1.4 | 0.0205 |
EIF4EBP1 | Eukaryotic Translation Initiation Factor 4E Binding Protein 1 | NM_001429.2:715 | PI3K | −1.3 | 0.0184 |
* MCM-7 | Minichromosome Maintenance Complex Component 7 | NM_182776.1:1325 | Cell-cycle Apoptosis | −1.7 | 0.00101 |
CCNA1 | Cyclin A1 | NM_003914.3:1605 | Cell-cycle Apoptosis | −1.4 | 0.0264 |
SMAD2 | SMAD Family Member 2 | NM_001003652.1:4500 | Cell-cycle Apoptosis | −1.4 | 0.0199 |
CHEK2 | Checkpoint Kinase 2 | NM_007194.3:140 | Cell-cycle Apoptosis | −1.3 | 0.0398 |
MAD2L2 | Mitotic Arrest Deficient 2 Like 2 | NM_001127325.1:290 | Cell-cycle Apoptosis | −1.3 | 0.0128 |
* SKP2 | S-Phase Kinase Associated Protein 2 | NM_005983.2:615 | Cell-cycle Apoptosis | −1.3 | 0.00026 |
CDC7 | Cell Division Cycle 7 | NM_003503.2:805 | Cell-cycle Apoptosis | −1.3 | 0.0302 |
RAD21 | RAD21 Cohesin Complex Component | NM_006265.2:1080 | Cell-cycle Apoptosis | −1.3 | 0.0289 |
* MAPT | Microtubule Associated Protein Tau | NM_016834.3:1205 | MAPK | −1.5 | 0.0469 |
RAC3 | Rac Family Small GTPase 3 | NM_005052.2:702 | MAPK | −1.4 | 0.0439 |
FLNA | Filamin A | NM_001456.3:7335 | MAPK | −1.3 | 0.00262 |
* PIK3CB | Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Beta | NM_006219.1:2945 | Cell cycle-apoptosis and PI3K | −1.3 | 0.0272 |
FAS | Fas Cell Surface Death Receptor | NM_152876.1:1740 | Cell cycle-apoptosis and MAPK | −1.4 | 0.00328 |
PPP3CA | Protein Phosphatase 3 Catalytic Subunit Alpha | NM_000944.4:3920 | Cell cycle-apoptosis and MAPK | −1.3 | 0.0223 |
* TGFB2 | Transforming Growth Factor Beta 2 | NM_003238.2:1125 | Cell cycle-apoptosis and MAPK | −1.6 | 0.0104 |
FGFR2 | Fibroblast Growth Factor Receptor 2 | NM_000141.4:647 | PI3K and MAPK | −1.6 | 0.0265 |
FGF2 | Fibroblast Growth Factor 2 | NM_002006.4:620 | PI3K and MAPK | −1.4 | 0.00307 |
FGFR4 | Fibroblast Growth Factor Receptor 4 | NM_002011.3:1585 | PI3K and MAPK | −1.3 | 0.027 |
* MAPK3 | Mitogen-Activated Protein Kinase 3 | NM_001040056.1:580 | PI3K and MAPK | −1.4 | 0.0425 |
TP53 | Tumor Protein P53 | NM_000546.2:1330 | Cell cycle-apoptosis, PI3K and MAPK | −1.3 | 0.00783 |
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Wan Mohd Tajuddin, W.N.B.; Abas, F.; Othman, I.; Naidu, R. Molecular Mechanisms of Antiproliferative and Apoptosis Activity by 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)1,4-Pentadiene-3-one (MS13) on Human Non-Small Cell Lung Cancer Cells. Int. J. Mol. Sci. 2021, 22, 7424. https://doi.org/10.3390/ijms22147424
Wan Mohd Tajuddin WNB, Abas F, Othman I, Naidu R. Molecular Mechanisms of Antiproliferative and Apoptosis Activity by 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)1,4-Pentadiene-3-one (MS13) on Human Non-Small Cell Lung Cancer Cells. International Journal of Molecular Sciences. 2021; 22(14):7424. https://doi.org/10.3390/ijms22147424
Chicago/Turabian StyleWan Mohd Tajuddin, Wan Nur Baitty, Faridah Abas, Iekhsan Othman, and Rakesh Naidu. 2021. "Molecular Mechanisms of Antiproliferative and Apoptosis Activity by 1,5-Bis(4-Hydroxy-3-Methoxyphenyl)1,4-Pentadiene-3-one (MS13) on Human Non-Small Cell Lung Cancer Cells" International Journal of Molecular Sciences 22, no. 14: 7424. https://doi.org/10.3390/ijms22147424