Role of protein tyrosine phosphorylation in etoposide-induced apoptosis and NF-kappa B activation.
When a human myeloid cell line, U937, was incubated with etoposide (10 micrograms/mL), morphologically apoptotic cells first appeared at 3 hr and increased with time to 50% at 6 hr. Pretreatment of U937 cells for 30 min with a potent tyrosine kinase inhibitor, herbimycin A (10 microM), significantly suppressed the appearance of apoptotic morphological changes. Concomitantly, herbimycin A pretreatment prevented both high molecular weight and internucleosomal DNA fragmentation induced by etoposide. Two major bands at 30 and 66 kDa with enhanced tyrosine phosphorylation inhibited by herbimycin A were detectable after 30 min of incubation with etoposide. In addition, herbimycin A prevented etoposide-induced NF-kappa B activation. The expressions of Bcl-2 and Bax, on the other hand, were not affected by herbimycin A pretreatment. Herbimycin A was also found to inhibit 1-beta-D-arabinofuranosylcytosine-induced apoptotic changes and NF-kappa B activation. These results suggest that activation of tyrosine kinase(s) may play an important role in apoptotic processes induced by a variety of anti-cancer drugs.
Usami
I
I
Department of Pediatrics, Faculty of Medicine, Kyoto University, Japan.
Kubota
M
M
Bessho
R
R
Kataoka
A
A
Koishi
S
S
Watanabe
K
K
Sawada
M
M
Lin
Y W
YW
Akiyama
Y
Y
Furusho
K
K
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D016227:Benzoquinones; D003561:Cytarabine / Q000494:pharmacology; D053938:DNA Fragmentation; D005047:Etoposide / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D047029:Lactams, Macrocyclic; D007951:Leukemia, Myeloid; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D011809:Quinones / Q000494:pharmacology; D017828:Rifabutin / Q000031:analogs & derivatives; D014407:Tumor Cells, Cultured; D051028:bcl-2-Associated X Protein
C494826:BAX protein, human; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D011809:Quinones; D051028:bcl-2-Associated X Protein; D003561:Cytarabine; D017828:Rifabutin; D019000:Phosphotyrosine; D005047:Etoposide; C020754:herbimycin; D011505:Protein-Tyrosine Kinases