K562 cell sensitization to 5-fluorouracil- or interferon-alpha-induced apoptosis via cordycepin (3'-deoxyadenosine): fine control of cell apoptosis via poly(A) polymerase upregulation.
K562 cells represent a classical model for the study of drug resistance. Induction of apoptosis is accompanied by concomitant distinct modulations of poly(A) polymerase (PAP) and other proteins involved in mRNA maturation. Recent data suggest the involvement of mRNA stability in the induction of specific apoptosis pathways. In this study we used a specific polyadenylation inhibitor, cordycepin (3-deoxyadenosine), to investigate the involvement of polyadenylation in K562 cell apoptosis and drug resistance. The combination of cordycepin with either 5-fluorouracil or interferon-alpha sensitized chemoresistant K562 cells to apoptosis. This sensitization was followed by distinct PAP modulations before and after the appearance of characteristic apoptosis pointers (DNA laddering, DAPI staining, mitochondrial transmembrane potential). PAP modulations appeared essential for K562 sensitization. mRNA polyadenylation therefore seemed to be involved not only in apoptosis but also in drug resistance. Polyadenylation inhibition by cordycepin under certain conditions sensitized chemoresistant K562 cells to apoptosis and thus polyadenylation could prove to be a fine target for overcoming drug resistance.
Lallas
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GC
Department of Biochemistry and Molecular Biology, Papanikolaou Research Center, St. Savvas Hospital, Athens, Greece. biochem@naf.forthnet.gr
Courtis
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N
Havredaki
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M
D017209:Apoptosis; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D002469:Cell Separation; D002470:Cell Survival; D004396:Coloring Agents / Q000494:pharmacology; D004247:DNA / Q000737:chemistry; D053938:DNA Fragmentation; D003839:Deoxyadenosines / Q000494:pharmacology*; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000494:pharmacology; D016898:Interferon-alpha / Q000494:pharmacology*; D020014:K562 Cells; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D026723:Polyadenylation; D011062:Polynucleotide Adenylyltransferase / Q000096:biosynthesis*; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D015854:Up-Regulation
D004396:Coloring Agents; D003839:Deoxyadenosines; D007211:Indoles; D016898:Interferon-alpha; D020033:Protein Isoforms; D012333:RNA, Messenger; D013778:Tetrazolium Salts; D013844:Thiazoles; C007293:DAPI; D004247:DNA; D011062:Polynucleotide Adenylyltransferase; C022616:thiazolyl blue; C058120:cordycepin; D005472:Fluorouracil