Proteo-stress induced by curcumin may confer resistance to the cytotoxicity of 4-hydroxy-2-nonenal

Proteo-stress refers to cellular stress caused by disturbances in proteostasis, such as an increase in unfolded or aggregated proteins, whereas its roles in biofunctions of phytochemicals remain to be fully elucidated. Zerumbone has previously been shown to bind to cellular proteins in a non-specific manner to cause proteo-stress and activate the protein quality control (PQC) systems. In this study, we aimed to identify other phytochemicals that have properties similar to zerumbone. The formation of p62/SQSTM1 protein oligomers was evaluated in a screening assay. Among 28 nutrients and phytochemicals, curcumin markedly increased the formation of p62/SQSTM1 oligomers. Treatment with curcumin increased denatured proteins in an insoluble protein fraction. Moreover, two housekeeping proteins degraded or insolubilized by curcumin and zerumbone, and they significantly induced the formation of aggresomes. The amounts of curcumin-generated abnormal proteins increased in a time-dependent manner and thereafter decreased, suggesting the activation of adaptive mechanisms for proteostasis. In fact, both zerumbone and curcumin markedly upregulated the expressions of heat shock proteins. They markedly suppressed cell death induced by 4-hydroxy-2-nonenal. Our results suggest that curcumin induces proteo-stress toward cellular proteins and the resultant activation of the PQC systems may protect the cell from proteo-toxic stimuli.