2-Deoxy-D-ribose inhibits hypoxia-induced apoptosis by suppressing the phosphorylation of p38 MAPK.
An angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (TP), stimulates the chemotaxis of endothelial cells and confers resistance to apoptosis induced by hypoxia. 2-Deoxy-d-ribose, a degradation product of thymidine generated by TP enzymatic activity, partially prevented hypoxia-induced apoptosis. 2-Deoxy-d-ribose inhibited hypoxia-induced phosphorylation of p38 mitogen-activated protein kinase (MAPK) but not c-jun NH(2)-terminal kinase/stress-activated protein kinase in human leukemia HL-60 cells. 2-Deoxy-d-ribose also suppressed the levels of Bax attached to mitochondria under hypoxic conditions. SB203580, a specific inhibitor of the p38 MAPK, suppressed the hypoxia-induced apoptosis of HL-60 cells. These findings suggest that one of the molecular bases for resistance to hypoxia-induced apoptosis conferred by 2-deoxy-d-ribose is the inhibition of the p38 signaling pathway. The expression levels of TP are elevated in many malignant solid tumors and thus the 2-deoxy-d-ribose generated by TP in these tumors may play an important role in tumor progression by preventing hypoxia-induced apoptosis.
Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8520, Japan.
Ryuji
R
Ikeda
Xiao-Fang
XF
Che
Mina
M
Ushiyama
Tatsuya
T
Yamaguchi
Hiroshi
H
Okumura
Yuichi
Y
Nakajima
Yasuo
Y
Takeda
Yoshihiko
Y
Shibayama
Tatsuhiko
T
Furukawa
Masatatsu
M
Yamamoto
Misako
M
Haraguchi
Tomoyuki
T
Sumizawa
Katsushi
K
Yamada
Shin-ichi
S
Akiyama
D017209:Apoptosis / Q000187:drug effects*; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D016764:Cell Polarity / Q000187:drug effects; D048430:Cell Shape; D003855:Deoxyribose / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D021381:Protein Transport; D011725:Pyridines / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D007093:Imidazoles; D011725:Pyridines; D051028:bcl-2-Associated X Protein; D003855:Deoxyribose; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580