Molecular basis for the inhibition of hypoxia-induced apoptosis by 2-deoxy-D-ribose.
An angiogenic factor, platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/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 inhibits a number of components of the caspase-mediated hypoxia-induced apoptotic pathway. It inhibits hypoxia-induced caspase 3 activation, mitochondrial cytochrome c release, downregulation of Bcl-2 and Bcl-x(L), upregulation of hypoxia-inducible factor (HIF)-1 alpha, and loss of mitochondrial transmembrane potential in human leukemia HL-60 cell line. These findings suggest a molecular mechanism by which 2-deoxy-d-ribose confers the resistance to apoptosis. Thus 2-deoxy-D-ribose-modulated suppression of HIF-1 alpha expression could prevent the hypoxia-induced decrease of the anti-apoptotic Bcl-2 and Bcl-x(L) on the mitochondria. 2-Deoxy-L-ribose and its analogs may enhance apoptosis and suppress the growth of tumors by competitively inhibiting the activities of 2-deoxy-d-ribose and thus these analogs show promise for anti-tumor therapy.
Ikeda
Ryuji
R
Department of Cancer Chemotherapy, Institute for Cancer Research, Kagoshima University, Sakuragaoka 8-35-1, Kagoshima 890-8520, Japan.
Furukawa
Tatsuhiko
T
Kitazono
Masaki
M
Ishitsuka
Kenji
K
Okumura
Hiroshi
H
Tani
Ayako
A
Sumizawa
Tomoyuki
T
Haraguchi
Misako
M
Komatsu
Masaharu
M
Uchimiya
Hiroshi
H
Ren
Xiao-Qin
XQ
Motoya
Toshiro
T
Yamada
Katsushi
K
Akiyama
Shin-ichi
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019556:COS Cells; D020169:Caspases / Q000378:metabolism; D015687:Cell Hypoxia; D003574:Cytochrome c Group / Q000378:metabolism; D003855:Deoxyribose / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008564:Membrane Potentials / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013939:Thymidine Phosphorylase / Q000037:antagonists & inhibitors; D014157:Transcription Factors / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism; D051020:bcl-X Protein
D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019253:Proto-Oncogene Proteins c-bcl-2; D014157:Transcription Factors; D025801:Ubiquitin; D051020:bcl-X Protein; D003855:Deoxyribose; D013939:Thymidine Phosphorylase; D020169:Caspases