Abstract
Arsenic is one of the environmental pollutants and a well-known carcinogen. Previous studies indicated that cytotoxicity caused by arsenic is recognized through generating oxidative stress, attenuating mitochondrial membrane potential, or influencing cell cycle to lead apoptosis. This study investigates the mechanism involved in the arsenic-induced cell death in Human Embryonic Kidney 293 (HEK 293) cells. Upon arsenic stimulation, PI3K/Akt signaling pathway is inhibited and leads to cytochrome c release from mitochondria which activates caspase 3 and apoptosis. However, PTEN is not participated in the PI3K/Akt signaling pathway. PTEN expression is reduced by arsenic treatment. Noticeably, the loss of PTEN is not due to the degradation of the protein, but presents in the insoluble fraction of the cells. The factor that assists protein refolding, heat shock protein 70 (Hsp 70), was also found in insoluble fraction. Concurrently, arsenic treatment inhibited the occurrence of autophagy in HEK 293 cells and caused an accumulation of LC3 in the cells. Administration of lysosomal activator (rapamycin) reduces the PTEN level in either soluble or insoluble fraction of the cells. The blockade of autophagy via reducing lysosomal activity caused the reduction of PI3K/Akt activity and led cells to apoptosis. Addition of rapamycin activates lysosomal activity and allows the cells to go through autophagy pathway. Our results reveal that arsenic treatment inhibits the lysosomal activity, and thus blocks the autophagy pathway. This blockade further reduces the activity of PI3K/Akt signaling pathway and leads to mitochondria-mediated apoptosis.