Non-Specific Protein Modifications by a Phytochemical Induce Heat Shock Response for Self-Defense

Abstract

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.

Role of Activating Transcription Factor 3 (ATF3) in Endoplasmic Reticulum (ER) Stress-induced Sensitization of p53-deficient Human Colon Cancer Cells to Tumor Necrosis Factor (TNF)-related Apoptosis-inducing Ligand (TRAIL)-mediated Apoptosis through Up-regulation of Death Receptor 5 (DR5) by Zerumbone and Celecoxib

“…The expression vector for CHOP was constructed by subcloning human CHOP cDNA into the pCIneo vector. ZER was obtained as described previously (36,37), and CCB was from SigmaAldrich (St. Louis, MO). Recombinant APO2/TRAIL was purchased from PeproTech (Rocky Hill NJ).…”

Allantopyrone A activates Keap1–Nrf2 pathway and protects PC12 cells from oxidative stress-induced cell death

“…Moreover, several compounds that have an α,β-unsaturated carbonyl moiety induce the expression of heat-shock proteins through non-specific binding to intracellular proteins. 18 Thus, we focused on the Keap1-Nrf2 system in this study. Allantopyrone A increased HO-1, and induced nuclear localization of Nrf2.…”

“…Some of the important thiol groups for Keap1 function include Cys151, Cys273 and Cys288, and each compound that directly binds to Keap1 target different combinations of thiol groups. 18 For example, sulforaphane and dimethyl fumarate are Cys151-preferring inducers and 15-deoxy-Δ 12,14 -prostaglandin J 2 is a Cys273/288-preferring inducer. Further studies are needed to elucidate which thiol groups of Keap1 are the direct target of allantopyrone A.…”

“…18 Indeed, dimethyl fumarate, a Keap1-Nrf2 activator that is used as a clinical drug for multiple sclerosis, acts by suppression of demyelination caused by the oxidative stress. In addition, development of Keap1-Nrf2 activators for diabetic nephropathy, age-related macular degeneration, has been carried out.…”

The Metabolic Plant Feedback Hypothesis: How Plant Secondary Metabolites Nonspecifically Impact Human Health

“…Consequently, nuclear receptors rather nonspecifically recognize lipophilic phytochemicals [38,39] as a loop function in the metabolic plant feedback. Nonspecific protein modifications and the induction of a "heat shock response" were shown to contribute to the effects of some phytochemicals [40,41]. Nevertheless, the bulk of phytochemicals are protein function inhibitors, at least in vitro.…”