Inhibition of PP2A and the consequent activation of JNK/c-Jun are involved in tributyltin-induced apoptosis in human amnionic cells.

Tributyltin (TBT), a highly toxic environmental contaminant, has been shown to induce mitochondrial-dependent apoptosis in several mammalian cells. However, the upstream signal transduction pathways involved in TBT-induced apoptosis are still not fully elucidated. In this study, the protein phosphatase (PP) 2A, microtubule organization, and mitogen-activated protein kinases (MAPKs), including JNK, p38 and their downstream transcription factors, c-Jun and ATF-2, respectively, were investigated in human amnionic cells treated by TBT. Furthermore, the activation of procaspase-3 after blocking either one of these MAPK pathways was also observed. The results showed that TBT effectively induced apoptosis characterized by caspase-3 activation. In apoptotic cells, the inhibition of PP2A activity and microtubule depolymerization was detected. Additionally, JNK and p38, as well as their downstream targets, c-Jun and ATF-2, were activated. Moreover, a JNK inhibitor, but not p38 inhibitor, significantly reduced caspase-3 activation. It can be concluded that the inhibition of PP2A may (1) play as a role in the activation of JNK and c-Jun and the concomitant promotion of microtubule depolymerization and (2) lead to the activation of caspase-3 in TBT-induced apoptotic cells. The results of this study suggest a critical role of PP2A in the TBT toxicity mechanism.