Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice
Abstract
:1. Introduction
2. Results
2.1. Significant Changes in the Transcriptome of Bladder Cancer Patient-Derived Xenografts are Associated with Drug Relapse Following Treatment.
2.2. MAT1A Expression Increases in Response to Chemotherapy in Bladder Cancer and Confers a Survival Advantage
2.3. MAT1A Confers a Survival Advantage, Potentially Through Decreases in Active Transcription and Proliferation
3. Discussion
4. Materials and Methods
4.1. Bladder Cancer Patient Derived Xenografts
4.2. Generation of Drug Relapsed PDX Tumors
4.3. RNA Sequencing
4.4. RNA Sequencing Data Analysis
4.5. Plasmid Transfection Generating 5637MAT1A+ Cells
4.6. Immunohistochemical Analysis
4.7. Human Patient Tissue Microarray Analysis (TMA)
4.8. The Human Protein Atlas: MAT1A
4.9. Western Blotting and Protein Analysis
4.10. In Vitro Toxicity
4.11. Quantitative PCR (qPCR)
4.12. Cell Proliferation
4.13. Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
MAT1A | Methionine adenosyltransferase 1a |
PDX | Patient-derived xenograft |
SAM | S-adenosylmethionine |
CIS | cisplatin |
GEM | gemcitabine |
NSG | NOD scid gamma |
Rx | drug treated |
PBS | phosphate buffered saline |
FC | fold change |
ATP | adenosine triphosphate |
PCR | polymerase chain reaction |
CFSE | carboxyfluorescein diacetate succinimidyl ester |
HCC | Hepatocellular carcinoma |
OPN | osteopontin |
SQ | subcutaneous |
IHC | immunohistochemical |
TMA | tissue microarrays |
FOLFIRINOX | Leucovorin, fluorouracil, irinotecan, oxaliplatin |
BCG | Bacillus Calmette-Guerin therapy |
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Ranking | Gene Symbol | Gene Name | BL0293_FC | BL0440_FC |
---|---|---|---|---|
1 | MAGEA11 | Melanoma-Associated Antigen 11 | 2.75 | 8.50 |
2 | MAT1A | Methionine Adenosyltransferase 1A | 6.66 | 3.40 |
3 | DIO2 | Iodothyronine Deiodinase 2 | 3.04 | 6.72 |
4 | PWWP2B | PWWP Domain-Containing Protein 2B | 4.91 | 3.67 |
5 | PAGE2 | Prostate-Associated Gene 2 Protein | 4.68 | 2.67 |
6 | FAM133A | Family With Sequence Similarity 133 Member A | 4.25 | 2.81 |
7 | ABHD17C | Abhydrolase Domain Containing 17C | 2.37 | 4.53 |
8 | LINC00839 | Long Intergenic Non-Protein Coding RNA 839 | 2.75 | 3.62 |
9 | OAS1 | 2′-5′-Oligoadenylate Synthetase 1 | 1.63 | 4.56 |
10 | RSAD2 | Radical S-Adenosyl Methionine Domain Containing 2 | 2.49 | 3.28 |
11 | CMPK2 | Cytidine/Uridine Monophosphate Kinase 2 | 1.80 | 3.67 |
12 | HMGN5 | High Mobility Group Nucleosome Binding Domain 5 | 2.80 | 2.49 |
13 | ZNF300P1 | Zinc Finger Protein 300 Pseudogene 1 | 2.64 | 1.91 |
14 | SEPT14 | Septin 14 | 1.75 | 2.57 |
15 | CEBPA | CCAAT Enhancer Binding Protein Alpha | 2.09 | 1.81 |
16 | KCNC4 | Potassium Voltage-Gated Channel Subfamily C Member 4 | 1.66 | 2.19 |
17 | NNMT | Nicotinamide N-Methyltransferase | 1.52 | 2.23 |
18 | MPC1 | Mitochondrial Pyruvate Carrier 1 | 1.69 | 1.71 |
19 | ZNF385B | Zinc Finger Protein 385B | 1.70 | 1.52 |
20 | CEBPD | CCAAT Enhancer Binding Protein Delta | 1.57 | 1.60 |
Reactome Identifier | Name | p-Value |
---|---|---|
R-HSA-909733 | Interferon alpha/beta signaling | 1.324 × 10-5 |
R-HSA-2408508 | Metabolism of ingested SeMet, Sec, MeSec into H2Se | 2.084 × 10-5 |
R-HSA-381340 | Transcriptional regulation of white adipocyte differentiation | 2.142 × 10-5 |
R-HSA-156581 | Methylation | 6.927 × 10-5 |
R-HSA-71291 | Metabolism of amino acids and derivatives | 2.613 × 10-3 |
R-HSA-156580 | Phase II conjugation | 3.383 × 10-3 |
R-HSA-2408522 | Selenoamino acid metabolism | 4.137 × 10-3 |
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Martin, K.A.; Hum, N.R.; Sebastian, A.; He, W.; Siddiqui, S.; Ghosh, P.M.; Pan, C.-x.; de Vere White, R.; Loots, G.G. Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice. Int. J. Mol. Sci. 2019, 20, 4983. https://doi.org/10.3390/ijms20204983
Martin KA, Hum NR, Sebastian A, He W, Siddiqui S, Ghosh PM, Pan C-x, de Vere White R, Loots GG. Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice. International Journal of Molecular Sciences. 2019; 20(20):4983. https://doi.org/10.3390/ijms20204983
Chicago/Turabian StyleMartin, Kelly A., Nicholas R. Hum, Aimy Sebastian, Wei He, Salma Siddiqui, Paramita M. Ghosh, Chong-xian Pan, Ralph de Vere White, and Gabriela G. Loots. 2019. "Methionine Adenosyltransferase 1a (MAT1A) Enhances Cell Survival During Chemotherapy Treatment and is Associated with Drug Resistance in Bladder Cancer PDX Mice" International Journal of Molecular Sciences 20, no. 20: 4983. https://doi.org/10.3390/ijms20204983