Antitumor activity of G-quadruplex-interactive agent TMPyP4 in K562 leukemic cells
2007
B270 Guanine (G)-quadruplexes are 4-stranded DNAs with stacks of G-quartets formed by 4 Gs in a planar structure through hydrogen bonding. Nucleic acid sequences with multiple G stretches tend to form thermodynamically stable G-quadruplexes. G-quadruplexes are present in the promoter or regulatory regions of important oncogenes, such as c-myc , c-myb , c-fos , and c-Abl , and in the single-stranded G-rich overhang of telomeres. These G-quadruplex structures may affect essential cellular processes. These findings suggest the G-quadruplex structure is a potential therapeutic target in leukemia. The cationic porphyrin TMPyP4 can bind to and stabilize DNA G-quadruplexes. We investigated the molecular mechanism of the antitumor activity of TMPyP4 in K562 cells and human telomere reverse transcriptase subunit (hTERT)-transfected K562 cells in which telomerase activity, followed by telomere elongation, was enhanced. Treatment with 100 µM TMPyP4 significantly inhibited the growth of both types of cell, with decreases in the G 1 phase and increases in the S and G 2 /M phases after 48 hours, preceding cell death after 72 hours. cDNA microarray analysis revealed upregulation of 33 genes and downregulation of 54 genes in K562 cells treated with 100 µM TMPyP4 for 48 hours. We found upregulation of 33 genes, including genes involved in cell cycle regulation ( p57 ); oncogenes ( growth-regulated oncogene [ GRO ] 1 and GRO3 ); stress-responsive genes ( growth arrest and DNA damage-inducible gene [ GADD ] 45B and GADD34 ); genes of adhesion molecules (intracellular adhesion molecule-1 [ ICAM1 ]; genes of calcium-binding proteins (calbindin 1 , S100 calcium-binding protein A10, and S100 calcium-binding protein A4 ); and genes for transcriptional regulation ( zinc finger protein 165 , zinc finger protein 76 , CCAAT enhancer binding protein [ C/EBP ] γ , and C/EBP β ). On the other hand, we found downregulation of 54 genes, including genes for cell-cycle regulation ( cyclin D2 , cyclin-dependent kinase [ CDK ] 5 , CDK8 , and p18 ); oncogenes ( pim-1 , pim-2 , and c-syn ); genes for DNA damage response ( topoisomerase I , topoisomerase II β , chromodomain helicase DNA binding protein 1 , and chromodomain helicase DNA-binding protein 4 ); for kinases ( adenylate kinase 2 , adenylate kinase 3 , Akt1 , PDZ-binding kinase , and protein kinase C β ); for adhesion molecules ( ICAM3 and CD58 ); for receptors ( fibroblast growth factor receptor 3 and insulin-like growth factor 1 receptor ); for ubiquitination ( ubiquitin-conjugating enzyme E2D1 , ubiquitin-conjugating enzyme E2M , ubiquitin carrier protein , and ubiquitin specific protease 7 ); and for transcriptional factors ( zinc finger protein 74 , general transcription factor IIIC , transcription factor 12 , forkhead transcription factor FOXL2 , c-myc , and v-myb ). Moreover, TMPyP4 decreased c-Myc protein expression, increased the expression of p21 CIP1 and p57 KIP2 proteins, and activated p38 mitogen-activated protein kinase, c-Jun N-terminal kinase, and extracellular signal-regulated kinase. These findings may provide a rationale for the development of G-quadruplex-interactive agents as novel antileukemic therapies.
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