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 wildtype 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.