Accumulated evidence shows that some phytochemicals provide beneficial effects for human health. Recently, a number of mechanistic studies have revealed that direct interactions between phytochemicals and functional proteins play significant roles in exhibiting their bioactivities. However, their binding selectivities to biological molecules are considered to be lower due to their small and simple structures. In this study, we found that zerumbone, a bioactive sesquiterpene, binds to numerous proteins with little selectivity. Similar to heat-denatured proteins, zerumbone-modified proteins were recognized by heat shock protein 90, a constitutive molecular chaperone, leading to heat shock factor 1-dependent heat shock protein induction in hepa1c1c7 mouse hepatoma cells. Furthermore, oral administration of this phytochemical up-regulated heat shock protein expressions in the livers of Sprague-Dawley rats. Interestingly, pretreatment with zerumbone conferred a thermoresistant phenotype to hepa1c1c7 cells as well as to the nematode Caenorhabditis elegans. It is also important to note that several phytochemicals with higher hydrophobicity or electrophilicity, including phenethyl isothiocyanate and curcumin, markedly induced heat shock proteins, whereas most of the tested nutrients did not. These results suggest that non-specific protein modifications by xenobiotic phytochemicals cause mild proteostress, thereby inducing heat shock response and leading to potentiation of protein quality control systems. We considered these bioactivities to be xenohormesis, an adaptation mechanism against xenobiotic chemical stresses. Heat shock response by phytochemicals may be a fundamental mechanism underlying their various bioactivities.
Zerumbone, a sesquiterpene present in Zingiber zerumbet Smith, has been implicated as a promising chemopreventive agent. Interestingly, a number of studies have revealed that its potent bioactivities are dependent on the electrophilic moiety of its ?,?-unsaturated carbonyl group, while our recent findings showed its chemical potential for binding to cellular proteins through a Michael reaction. In the present study, modifications of proteins by zerumbone led to their insolubilization in vitro. In living cell models, zerumbone induced ubiquitination and aggregation of cellular proteins, which demonstrated its substantial proteo-toxicity. On the other hand, it was also revealed that zerumbone possesses potential for activating intracellular proteolysis mechanisms of the ubiquitin-proteasome system and autophagy. Furthermore, it up-regulated expressions of pro-autophagic genes including p62, which is known as a cargo receptor of aggrephagy, the selective autophagic process for protein aggregates. Pretreatment of Hepa1c1c7 cells with zerumbone conferred a phenotype resistant to cytotoxicity and protein modifications by 4-hydroxy-2-nonenal, an endogenous lipid peroxidation product, in a p62-dependent manner. Together, these results suggest that protein modifications by zerumbone cause mild proteo-stress, thereby activating intracellular proteolysis machineries to maintain protein homeostasis. We consider these effects on proteolysis mechanisms to be hormesis, which provides beneficial functions through mild biological stresses.
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