Protein tyrosine kinase Lyn mediates apoptosis induced by topoisomerase II inhibitors in DT40 cells.
Several sets of non-receptor protein tyrosine kinases (PTK) play important roles in apoptosis induced by various extracellular stresses. Anti-cancer drugs induce cellular DNA damage and cytotoxic events, leading to apoptotic cell death. We utilized the established chicken B cell line, DT40 cells and their derived mutants, lacking the respective PTK [DT40/Syk(-), DT40/Lyn(-) and DT40/Btk(-)], to examine a role of these PTK in apoptotic processes induced by anti-cancer drugs. All anti-cancer drugs examined induced apoptosis of wild-type DT40 cells. Interestingly,DT40/Lyn(-), but not DT40/Syk(-) and DT40/Btk(-) cells, become resistant to apoptosis induced by adriamycin and etoposide, topoisomerase II (Topo II) inhibitory agents, compared to wild-type DT40 cells, as assessed by DNA fragmentation and TUNEL analyses. Ectopic expression of Fyn, another Src family member, in DT40/Lyn(-) cells restores largely the susceptibility of the cells against Topo II inhibitor-induced apoptosis. Furthermore, it was found that Topo II inhibitors activate c-Jun N-terminal kinase (JNK) slightly in both wild-type and DT40/Lyn(-) cells to similar extents. Collectively, these results suggest that Lyn is involved in Topo II inhibitor-induced apoptotic signaling in DT40 cells independent of JNK.
Maruo
A
A
Department of Biochemistry, Kobe University, School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
Oishi
I
I
Sada
K
K
Nomi
M
M
Kurosaki
T
T
Minami
Y
Y
Yamamura
H
H
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002460:Cell Line / Q000187:drug effects; D002645:Chickens; D053938:DNA Fragmentation; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases / Q000032:analysis / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D059005:Topoisomerase II Inhibitors; D019061:src-Family Kinases / Q000172:deficiency / Q000502:physiology*
D000970:Antineoplastic Agents; D009363:Neoplasm Proteins; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D004317:Doxorubicin; D011505:Protein-Tyrosine Kinases; C490512:Frk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D004250:DNA Topoisomerases, Type II