Pharmacologic downregulation of protein arginine methyltransferase1 expression by adenosine dialdehyde increases cell senescence in breast cancer

Autor: Jesu Arockiaraj, Naif Abdullah Al-Dhabi, Ganesh Munusamy-Ramanujam, N.T. Saraswathi, Aziz Arshad, Mariadhas Valan Arasu, Thirumurthy Madhavan, Soniya Charles, Kanchana Mala, Priya Singh
Rok vydání: 2020
Předmět:
0301 basic medicine
Protein-Arginine N-Methyltransferases
Methyltransferase
Adenosine
Arginine
Phosphatidylethanolamine N-Methyltransferase
Cell
Estrogen receptor
Down-Regulation
Breast Neoplasms
Pharmacology
Methylation
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
stomatognathic system
Downregulation and upregulation
Antineoplastic Combined Chemotherapy Protocols
medicine
Humans
Cellular Senescence
Cell Proliferation
Drug Synergism
Cell Cycle Checkpoints
Gene Expression Regulation
Neoplastic
Molecular Docking Simulation
Repressor Proteins
Oxidative Stress
Tamoxifen
030104 developmental biology
medicine.anatomical_structure
chemistry
Betaine-Homocysteine S-Methyltransferase
MCF-7 Cells
Female
Asymmetric dimethylarginine
Protein Processing
Post-Translational
030217 neurology & neurosurgery
medicine.drug
Signal Transduction
Zdroj: European journal of pharmacology. 891
ISSN: 1879-0712
Popis: We investigated the role of protein arginine methylation (PAM) in estrogen receptor (ER)-positive breast cancer cells through pharmacological intervention. Tamoxifen (TAM) or adenosine dialdehyde (ADOX), independently, triggered cell cycle arrest and down-regulated PAM, as reduced protein arginine methyltransferase1 (PRMT1) mRNA and asymmetric dimethylarginine (ADMA) levels. Synergistic effect of these compounds elicited potent anti-cancer effect. However, reduction in ADMA was not proportionate with the compound-induced down-regulation of PRMT1 mRNA. We hypothesized that the disproportionate effect is due to the influence of the compounds on other methyltransferases, which catalyze the arginine dimethylation reaction and the diversity in the degree of drug-protein interaction among these methyltransferases. In silico analyses revealed that independently, ADOX or TAM, binds with phosphatidylethanolamine-methyltransferase (PEMT) or betaine homocysteine-methyl transferase (BHMT); and that the binding affinity of ADOX with PEMT or BHMT is prominent than TAM. These observations suggest that in breast cancer, synergistic effect of ADOX + TAM elicits impressive protective function by regulating PAM; and plausibly, restoration of normal enzyme activities of methyltransferases catalyzing arginine dimethylation could have clinical benefits.
Databáze: OpenAIRE
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