The role of protein kinase C alpha in tri‐ortho‐cresyl phosphate‐induced autophagy in human neuroblastoma SK‐N‐SH cells

As an organophosphorus ester, tri‐ortho‐cresyl phosphate (TOCP) has been widely used in agriculture and industry. It is reported that TOCP can induce organophosphate‐induced delayed neuropathy (OPIDN) in sensitive animal and human species. However, the exact molecular mechanisms underlying TOCP‐induced neurotoxicity are still unknown. In this study, we found that TOCP could induce autophagy by activating protein kinase C alpha (PKCα) signaling in neuroblastoma SK‐N‐SH cells. PKCα activators could positively regulate TOCP‐induced autophagy by increasing the expression levels of neighbor BRCA1 gene protein 1 (NBR1), LC3 and P62 autophagic receptor protein. Furthermore, PKCα activation impaired the ubiquitin‐proteasome system (UPS), resulting in inhibition of proteasome activity and accumulation of ubiquitinated proteins. UPS dysfunction could stimulate autophagy to serve as a compensatory pathway, which contributed to the accumulation of the abnormally hyperphosphorylated tau proteins and degradation of impaired proteins of the MAP 2 and NF‐H families in neurodegenerative disorders. TOCP regulates autophagy by activated PKCα