title: p38 mitogen-activated protein kinase is a key regulator of 5-phenylselenyl- and 5-methylselenyl-methyl-2'-deoxyuridine-induced apoptosis in human HL-60 cells.
abstract: Two novel, modified thymidine nucleosides, 5-phenylselenyl-methyl-2'-deoxyuridine (PhSe-T) and 5-methylselenyl-methyl-2'-deoxyuridine (MeSe-T), trigger reactive oxygen species (ROS) generation and DNA damage and thereby induce caspase-mediated apoptosis in human HL-60 cells; however, the mechanism leading to caspase activation and apoptotic cell death remains unclear. Therefore, we investigated the signaling molecules involved in nucleoside derivative-induced caspase activation and apoptosis in HL-60 cells. PhSe-T/MeSe-T treatment activated two mitogen-activated protein kinases (MAPKs), extracellular-receptor kinase (ERK) and p38, and induced the phosphorylation of two downstream targets of p38, ATF-2 and MAPKAPK2. In addition, the selective p38 inhibitor SB203580 suppressed PhSe-T/MeSe-T-induced apoptosis and activation of caspase-3, -9, -8, and -2, whereas the jun amino-terminal kinase (JNK) inhibitor SP600125 and the ERK inhibitor PD98059 had no effect. SB203580 and an ROS scavenger, tiron, inhibited PhSe-T/MeSe-T-induced histone H2AX phosphorylation, which is a DNA damage marker. Moreover, tiron inhibited PhSe-T/MeSe-T-induced phosphorylation of p38 and enhanced p38 MAP kinase activity, indicating a role for ROS in PhSe-T/MeSe-T-induced p38 activation. Taken together, our results suggest that PhSe-T/MeSe-T-induced apoptosis is mediated by the p38 pathway and that p38 serves as a link between ROS generation and DNA damage/caspase activation in HL-60 cells.
authors.affiliation: Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Seoul, Republic of Korea.
authors.forename: Byeong Mo
authors.initials: BM
authors.lastname: Kim
authors.forename: Kee-Ho
authors.initials: KH
authors.lastname: Lee
authors.forename: In Seok
authors.initials: IS
authors.lastname: Hong
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Hong
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D053143:Caspase 2 / Q000096:biosynthesis; D053148:Caspase 3 / Q000096:biosynthesis; D053181:Caspase 8 / Q000096:biosynthesis; D004249:DNA Damage; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D016566:Organoselenium Compounds / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C558288:5-methylselenylmethyl-2'-deoxyuridine; C558289:5-phenylselenylmethyl-2'-deoxyuridine; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D016566:Organoselenium Compounds; D011725:Pyridines; D017382:Reactive Oxygen Species; D011065:Poly(ADP-ribose) Polymerases; D048051:p38 Mitogen-Activated Protein Kinases; D053143:Caspase 2; D053148:Caspase 3; D053181:Caspase 8; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D003857:Deoxyuridine