Arsenic trioxide promotes ERK1/2-mediated phosphorylation and degradation of BIM to attenuate apoptosis in BEAS-2B cells.

Inorganic arsenic is highly toxic, widely distributed in the human environment and may result in multisystem diseases and several types of cancers. The BCL-2-interacting mediator of cell death protein (BIM) is a key modulator of the intrinsic apoptosis pathway. Interestingly, in the present study, we found that arsenic trioxide (AsO) decreased BIM levels in human bronchial epithelial cell line BEAS-2B and increased BIM levels in human lung carcinoma cell line A549 and mouse Sertoli cell line TM4. Mechanismly, the 26S proteasome inhibitors MG132 and bortezomib could effectively inhibit BIM degradation induced by AsO in BEAS-2B cells. AsO activated extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) signaling pathways, but only the ERK1/2 MAPK inhibitor PD98059 blocked BIM degradation induced by AsO. Furthermore, AsO induced-phosphorylation of BIM at multiple sites was inhibited by ERK1/2 MAPK inhibitor PD98059. Inhibition of AsO-induced ERK1/2 MAPK phosphorylation increased the levels of BIM and cleaved-caspase-3 proteins and decreased BEAS-2B cell viability. AsO also markedly mitigated tunicamycin-induced apoptosis of BEAS-2B cells by increasing ERK1/2 phosphorylation and BIM degradation. Our results suggest that AsO-induced activation of the ERK1/2 MAPK pathway increases phosphorylation of BIM and promotes BIM degradation, thereby alleviating the role of apoptosis in AsO-induced cell death. This study provides new insights into how to maintain the survival of BEAS-2B cells before malignant transformation induced by high doses of AsO.