Etoposide-induced activation of c-jun N-terminal kinase (JNK) correlates with drug-induced apoptosis in salivary gland acinar cells

We have examined the ability of etoposide to induce apoptosis in two recent ly established rat salivary acinar cell lines. Etoposide induced apoptosis in the parotid C5 cell line as evidenced by the appearance of cytoplasmic b lebbing and nuclear condensation, DNA fragmentation and cleavage of PARP, E toposide also induced activation of c-jun N-terminal kinase (JNK) in paroti d C5 cells by 4 h after treatment, with maximal activation at 8-10 h, Coinc ident with activation of JNK, the amount of activated ERK1 and ERK2 decreas ed in etoposide-treated parotid C5 cells. In contrast to the parotid C5 cel ls, the vast majority of submandibular C6 cells appeared to be resistant to etoposide-induced apoptosis, Likewise, activation of JNKs was not observed in etoposide-treated submandibular C6 cells, and the amount of activated E RK1 and ERK2 decreased only slightly. Etoposide treatment of either cell li ne had no effect upon the activation of p38, Treatment of the parotid C5 ce lls with Z-VAD-FMK, a caspase inhibitor, inhibited etoposide-induced activa tion of JNK and DNA fragmentation. These data suggest that etoposide may in duce apoptosis in parotid C5 cells by activating JNKs and suppressing the a ctivation of ERKs, thus creating an imbalance in these two signaling pathwa ys.