title: 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.
authors.affiliation: Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto, Japan.
authors.forename: Kohta
authors.initials: K
authors.lastname: Ohnishi
authors.forename: Shinya
authors.initials: S
authors.lastname: Ohkura
authors.forename: Erina
authors.initials: E
authors.lastname: Nakahata
authors.forename: Akari
authors.initials: A
authors.lastname: Ishisaka
authors.forename: Yoshichika
authors.initials: Y
authors.lastname: Kawai
authors.forename: Junji
authors.initials: J
authors.lastname: Terao
authors.forename: Taiki
authors.initials: T
authors.lastname: Mori
authors.forename: Takeshi
authors.initials: T
authors.lastname: Ishii
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Nakayama
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kioka
authors.forename: Shinya
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Yasutaka
authors.initials: Y
authors.lastname: Ikeda
authors.forename: Minoru
authors.initials: M
authors.lastname: Akiyama
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Irie
authors.forename: Akira
authors.initials: A
authors.lastname: Murakami
mesh_terms: D000220:Adaptation, Biological / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D018841:HSP90 Heat-Shock Proteins / Q000378:metabolism; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000378:metabolism; D018869:Heat-Shock Response / Q000187:drug effects* / Q000502:physiology*; D008297:Male; D051379:Mice; D010641:Phenotype; D011485:Protein Binding; D011506:Proteins / Q000737:chemistry / Q000378:metabolism*; D051381:Rats; D012717:Sesquiterpenes / Q000378:metabolism / Q000494:pharmacology*; D013696:Temperature; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D018841:HSP90 Heat-Shock Proteins; D000076249:Heat Shock Transcription Factors; D006360:Heat-Shock Proteins; C490017:Hsf1 protein, mouse; D011506:Proteins; D012717:Sesquiterpenes; D014157:Transcription Factors; C403304:zerumbone
references.citation: Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3059-64
references.pmid: 19223593
references.citation: Cell Stress Chaperones. 2003 Spring;8(1):1-7
references.pmid: 12820649
references.citation: Adv Exp Med Biol. 2007;594:89-99
references.pmid: 17205678
references.citation: Int J Hyperthermia. 1995 Sep-Oct;11(5):697-708
references.pmid: 7594820
references.citation: Int J Cancer. 2007 Dec 1;121(11):2357-63
references.pmid: 17893865
references.citation: Mol Nutr Food Res. 2009 Dec;53(12):1540-50
references.pmid: 19904761
references.citation: Genetics. 1974 May;77(1):71-94
references.pmid: 4366476
references.citation: J Biol Chem. 2008 Apr 4;283(14):9424-34
references.pmid: 18199750
references.citation: J Biol Chem. 1998 Jul 10;273(28):17954-61
references.pmid: 9651402
references.citation: Chem Res Toxicol. 2008 Oct;21(10):1991-6
references.pmid: 18729326
references.citation: Biosci Biotechnol Biochem. 1999 Oct;63(10):1811-2
references.pmid: 10586508
references.citation: Carcinogenesis. 2008 Apr;29(4):807-15
references.pmid: 18204073
references.citation: BMC Biochem. 2005 Mar 11;6:4
references.pmid: 15760475
references.citation: Carcinogenesis. 2002 May;23(5):795-802
references.pmid: 12016152
references.citation: J Biol Chem. 2010 Nov 12;285(46):35528-36
references.pmid: 20833711
references.citation: Cell Metab. 2008 Mar;7(3):200-3
references.pmid: 18316025
references.citation: J Biol Chem. 2011 Dec 9;286(49):42150-42161
references.pmid: 21998322
references.citation: Eur J Biochem. 1991 Jul 1;199(1):35-9
references.pmid: 1712300
references.citation: Cell. 1991 May 3;65(3):363-6
references.pmid: 2018972
references.citation: J Biol Chem. 2007 Nov 16;282(46):33412-33420
references.pmid: 17873279
references.citation: Metabolism. 2011 Jun;60(6):789-98
references.pmid: 20817212
references.citation: BMC Cancer. 2010 Jun 10;10:276
references.pmid: 20537126
references.citation: Anal Biochem. 1982 Oct;126(1):131-8
references.pmid: 7181105
references.citation: FEBS Lett. 2004 Aug 13;572(1-3):245-50
references.pmid: 15304356
references.citation: Nat Struct Mol Biol. 2004 Apr;11(4):380-1
references.pmid: 15024383
references.citation: Carcinogenesis. 2012 Jan;33(1):2-9
references.pmid: 22080571
references.citation: Cell. 2008 May 2;133(3):387-91
references.pmid: 18455976
references.citation: Nat Rev Mol Cell Biol. 2008 Sep;9(9):679-90
references.pmid: 18698327
references.citation: J Natl Cancer Inst. 1996 Nov 6;88(21):1560-70
references.pmid: 8901854
references.citation: Biosci Biotechnol Biochem. 2009 Aug;73(8):1905-7
references.pmid: 19661711
references.citation: Ann N Y Acad Sci. 2011 Jul;1229:1-6
references.pmid: 21793832
references.citation: Am J Pathol. 2011 Dec;179(6):2822-34
references.pmid: 22001349
references.citation: Proc Natl Acad Sci U S A. 2005 Sep 13;102(37):13135-40
references.pmid: 16141322
references.citation: J Cell Physiol. 2010 May;223(2):408-14
references.pmid: 20082303
references.citation: J Nutr. 2005 Dec;135(12 Suppl):2987S-2992S
references.pmid: 16317159
references.citation: Phytochemistry. 2003 Sep;64(1):3-19
references.pmid: 12946402
references.citation: Proc Natl Acad Sci U S A. 1979 Mar;76(3):1333-7
references.pmid: 286315
references.citation: Dev Biol. 1973 Nov;35(1):83-96
references.pmid: 4362668
references.citation: J Biol Chem. 2008 Aug 8;283(32):22136-46
references.pmid: 18524779
references.citation: FEBS Lett. 2003 Feb 27;537(1-3):139-45
references.pmid: 12606046
references.citation: Am J Physiol Cell Physiol. 2010 Jan;298(1):C171-81
references.pmid: 19846753
references.citation: Nat Chem Biol. 2011 Jul 03;7(8):538-43
references.pmid: 21725302
references.citation: Biofactors. 2010 Jan-Feb;36(1):43-51
references.pmid: 20108331
references.citation: Int J Cancer. 2009 Jan 15;124(2):264-71
references.pmid: 19003968
references.citation: Mol Aspects Med. 2009 Feb-Apr;30(1-2):29-41
references.pmid: 18786561
references.citation: Biochem Biophys Res Commun. 1999 Nov 30;265(3):763-9
references.pmid: 10600494
references.citation: Front Biosci (Schol Ed). 2011 Jun 01;3:1332-62
references.pmid: 21622274
references.citation: Mol Cell Biol. 1993 Apr;13(4):2486-96
references.pmid: 8455624