Protein tyrosine kinase Lyn mediates apoptosis induced by topoisomerase IIinhibitors in DT40 cells

Several sets of non-receptor protein tyrosine kinases (PTK) play important roles in apoptosis induced by various extracellular stresses. Anti-cancer d rugs 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 i nduced by anti-cancer drugs. All anti-cancer drugs examined induced apoptos is 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 w ildtype DT40 cells, as assessed by DNA fragmentation and TUNEL analyses. Ec topic expression of Fyn, another Src family member, in DT40/Lyn(-) cells re stores largely the susceptibility of the cells against Topo II inhibitor-in duced apoptosis, Furthermore, it was found that Topo II inhibitors activate c-Jun N-terminal kinase (JNK) slightly in both wild-type and DT40/Lyn(-) c ells to similar extents. Collectively, these results suggest that Lyn is in volved in Topo II inhibitor-induced apoptotic signaling in DT40 cells indep endent of JNK.