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

Abstract

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.

Tributyltin induces disruption of microfilament in HL7702 cells via MAPK‐mediated hyperphosphorylation of VASP

“…However, unlike the previous studies, P38 was not activated. Actually, in Zhang's study (Zhang et al, ), although JNK and P38 were activated in response to TBT, surprisingly, while JNK inhibitors were able to induce a response to significantly reduce caspase‐3 activation, P38 inhibitors were not, suggesting that P38 does not seem to play a pivotal role in regulating cell death. In the current study, inhibition of ERK and JNK not only largely diminished the TBT‐induced hyperphosphorylation of VASP but also recovered the cellular morphology and rescued cells from death.…”

“…A wealth of studies have confirmed that TBT causes disruption of actin filaments (Cima and Ballarin, 2000;Tsukazaki et al, 2004;Zhu et al, 2007;Zhang et al, 2013), which may be the key factor that triggers apoptosis (Cabado et al, 2004). Changes in cell morphology are associated with reorganization of actin filaments, mostly depending on their intrinsic ability to rapidly assemble and disassemble, indicating a key role of the actin cytoskeleton in the complex network that engages membrane-related events and signal transduction cascades (Cabado et al, 2004;Ferreira et al, 2013).…”

“…In human amnionic cells, treatment with 4 μM TBT for 2 h led to obvious F‐actin depolymerization (Zhu et al, ). When the concentration of TBT increased to 6 μM, significant reduction of microtubule density and a disappearance of tubulin filaments in the cytoplasm were observed, which were due to decreased levels of acetylated tubulin (Zhang et al, ).…”

“…It not only maintains the cellular morphology but also plays important roles in signal transduction (Wickstead and Gull, 2011). Previous studies have indicated that TBT can cause cytoskeletal disruption both in vitro and in vivo (Cima et al, 1998;Cima and Ballarin, 2000;Zhu et al, 2007;Zhang et al, 2013). For example, in colonial ascidian Botryllus schlosseri phagocytes, 10 lM TBT causes considerable structural damage of cytoskeletal components, including extensive depolymerization of F-actin and disruption of microtubules (Cima and Ballarin, 2000).…”

Effects of cerulein on keratin 8 phosphorylation and perinuclear reorganization in pancreatic cancer cells: Involvement of downregulation of protein phosphatase 2A and alpha4

“…These reports suggested that upstream players of both JNK and ERK might be involved in this process. Therefore, since PP2A can dephosphorylate both JNK and ERK, leading to inactivation of JNK and ERK and, directly, to dephosphorylation of K8 pSer431, we examined the effects of cerulein on PP2A expression (Tao et al, ; Levallet et al, ; Zhang et al, ). As expected, cerulein reduced the expression of PP2A [Fig.…”