The interaction of Atg4B and Bcl-2 plays an important role in Cd-induced crosstalk between apoptosis and autophagy through disassociation of Bcl-2-Beclin1 in A549 cells

Abstract

Cadmium (Cd) is a highly ubiquitous detrimental metal in the environment. It is a well-known inducer of tumorigenesis, but the mechanism is not clear. In our previous study, we found that ROS-dependent Atg4B upregulation mediated Cd-induced autophagy and autophagy played an important role in Cd-induced proliferation and invasion in A549 cells. In this study, we found that Cd induced both apoptosis and autophagy in A549 cells, and apoptosis preceded autophagy. Z-VAD-FMK repressed Cd-induced LC3 and Beclin1, indicating that apoptosis was essential for Cd-induced autophagy. 3MA destroyed the recovery of mitochondrial membrane potential and increased Cd-induced CL-CASP9 and CL-CASP3 expression, suggesting that Cd-induced autophagy prevented A549 cells from apoptosis. Further study showed that Atg4B upregulation was mediated by mitochondrial dysfunction and conversely affected mitochondrial function by decreasing Bcl-2 protein expression and its localization in mitochondria, and played an important role in Cd-induced apoptosis. Moreover, Bcl-2 was involved in Cd-induced autophagy. Co-IP assay showed that Atg4B could directly bind to Bcl-2, and consequently promote disassociation of Bcl-2-Beclin1 and released autophagic protein Beclin1 to activate autophagic pathway. Taken together, our results demonstrated that the interaction of Atg4B and Bcl-2 might play an important role in Cd-induced crosstalk between apoptosis and autophagy through disassociation of Bcl-2-Beclin1. Cd-induced autophagy is apoptosis-dependent and prevents apoptotic cell death to ensure the growth and proliferation of A549 cells.