title: Curcuminoids activate p38 MAP kinases and promote UVB-dependent signalling in keratinocytes.
abstract: Curcuminoids exhibit anti-proliferative properties in many cell lines by modulating signalling pathways to inhibit cell growth. However, the specific effects of curcuminoids on human keratinocytes are not well defined, and this situation impairs mechanistic thinking regarding potential therapeutic uses. We hypothesized that curcuminoids would modulate key growth regulatory pathways in keratinocytes to inhibit cell proliferation. To test this hypothesis, the effects of curcumin and tetrahydrocurcumin (THC) on mitogen-activated protein (MAP) kinase signalling in keratinoctyes were determined. Primary human keratinocytes treated with curcumin or THC demonstrated decreased activation of p44/42 MAP kinases but increased levels of activated p38 MAP kinases. These data suggest that curcuminoids specifically activate stress-induced MAP kinases while inhibiting mitogen-induced MAP kinases. Curcuminoids also promote the phosphorylation of p53 on serine 15 in a dose-dependent and p38-dependent manner, suggesting that these compounds may activate p53. The effects of curcuminoids on keratinocytes mirrored some aspects of UVB and could be inhibited by N-acetylcysteine, suggesting that these compounds activate p38 through a mechanism that involves glutathione depletion. Both curcuminoids induced G2/M block and inhibited keratinocyte growth, and THC increased cellular levels of p21, a known p53 transcriptional target. These data demonstrate that curcuminoids can differentially regulate MAP kinases to inhibit keratinocyte growth while inducing p21. Curcuminoids also synergize with UVB to enhance p53 phosphorylation. The findings provide a rationale for testing curcuminoids in disorders associated with impaired p53 function or in which UVB-treatment is efficacious.
authors.affiliation: Department of Dermatology, University of Pennsylvania Medical School, Philadelphia, PA, USA.
authors.forename: Elias E
authors.initials: EE
authors.lastname: Ayli
authors.forename: Susanne
authors.initials: S
authors.lastname: Dugas-Breit
authors.forename: Weijie
authors.initials: W
authors.lastname: Li
authors.forename: Christine
authors.initials: C
authors.lastname: Marshall
authors.forename: Liang
authors.initials: L
authors.lastname: Zhao
authors.forename: Marc
authors.initials: M
authors.lastname: Meulener
authors.forename: Thomas
authors.initials: T
authors.lastname: Griffin
authors.forename: Joel M
authors.initials: JM
authors.lastname: Gelfand
authors.forename: John T
authors.initials: JT
authors.lastname: Seykora
mesh_terms: D000111:Acetylcysteine / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007399:Interphase / Q000187:drug effects; D015603:Keratinocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D008954:Models, Biological; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects* / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D007093:Imidazoles; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D016159:Tumor Suppressor Protein p53; C096277:tetrahydrocurcumin; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; D005978:Glutathione; D003474:Curcumin; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole; D000111:Acetylcysteine
references.citation: Int J Oncol. 2005 Jun;26(6):1597-603
references.pmid: 15870875
references.citation: J Am Acad Dermatol. 2008 Apr;58(4):625-31
references.pmid: 18249471
references.citation: Mol Cell Biol. 1997 Aug;17(8):4792-800
references.pmid: 9234735
references.citation: Cancer. 2005 Aug 15;104(4):879-90
references.pmid: 16007726
references.citation: Oncogene. 2001 Mar 1;20(9):1076-84
references.pmid: 11314044
references.citation: Cell Cycle. 2007 Dec 1;6(23):2928-31
references.pmid: 18000402
references.citation: Biochem Pharmacol. 2004 Sep 15;68(6):1125-31
references.pmid: 15313409
references.citation: J Neurooncol. 2007 Dec;85(3):263-70
references.pmid: 17594054
references.citation: Invasion Metastasis. 1996;16(1):3-10
references.pmid: 8830760
references.citation: Biochem Pharmacol. 1996 Jan 12;51(1):39-45
references.pmid: 8534266
references.citation: J Cell Biochem Suppl. 1997;27:26-34
references.pmid: 9591190
references.citation: Nature. 1994 Dec 22-29;372(6508):773-6
references.pmid: 7997263
references.citation: Oncol Rep. 1998 Mar-Apr;5(2):507-12
references.pmid: 9468590
references.citation: Cancer Epidemiol Biomarkers Prev. 1997 Aug;6(8):583-7
references.pmid: 9264270
references.citation: Lancet. 1994 Sep 17;344(8925):788-9
references.pmid: 7916075
references.citation: Biochem J. 2002 Jul 1;365(Pt 1):133-45
references.pmid: 12071847
references.citation: Biochem Pharmacol. 2007 Apr 1;73(7):1024-32
references.pmid: 17240359
references.citation: In Vitro Cell Dev Biol Anim. 2003 Jan-Feb;39(1-2):36-42
references.pmid: 12892525
references.citation: J Invest Dermatol. 2007 Aug;127(8):1992-2000
references.pmid: 17410200
references.citation: Cancer Res. 2006 Mar 1;66(5):2700-7
references.pmid: 16510590
references.citation: J Biol Chem. 2005 Feb 18;280(7):6036-46
references.pmid: 15579470
references.citation: Oncogene. 1996 Jun 20;12(12):2483-90
references.pmid: 8700506
references.citation: Anticancer Res. 2003 Jan-Feb;23(1A):363-98
references.pmid: 12680238
references.citation: Melanoma Res. 2004 Jun;14(3):165-71
references.pmid: 15179184
references.citation: Int J Oncol. 2002 Aug;21(2):379-83
references.pmid: 12118335
references.citation: Lipids. 1997 Nov;32(11):1173-80
references.pmid: 9397403
references.citation: Carcinogenesis. 1995 Aug;16(8):1741-5
references.pmid: 7634398
references.citation: J Invest Dermatol. 1999 May;112(5):751-6
references.pmid: 10233767
references.citation: Oncogene. 2007 May 14;26(22):3291-310
references.pmid: 17496923
references.citation: J Clin Invest. 2007 Dec;117(12):3753-64
references.pmid: 18060030
references.citation: Exp Hematol. 1997 May;25(5):413-22
references.pmid: 9168063
references.citation: Oncol Rep. 2006 May;15(5):1225-31
references.pmid: 16596191
references.citation: Oncogene. 2000 Jan 20;19(3):358-64
references.pmid: 10656682
references.citation: Food Chem Toxicol. 2002 Aug;40(8):1091-7
references.pmid: 12067569
references.citation: Lancet. 1988 Apr 9;1(8589):795-7
references.pmid: 2895318
references.citation: Cell. 1997 Oct 31;91(3):325-34
references.pmid: 9363941
references.citation: Anticancer Res. 1999 Sep-Oct;19(5A):3675-80
references.pmid: 10625938
references.citation: Cell. 1993 Nov 19;75(4):817-25
references.pmid: 8242752
references.citation: Nutr Cancer. 2004;49(2):200-8
references.pmid: 15489213
references.citation: J Cutan Med Surg. 2002 May-Jun;6(3):207-9
references.pmid: 11951126
references.citation: J Biol Chem. 2005 May 20;280(20):20059-68
references.pmid: 15738001
references.citation: J Biol Chem. 2007 Jan 12;282(2):1161-9
references.pmid: 17046829
references.citation: Br J Dermatol. 2007 May;156 Suppl 3:34-9
references.pmid: 17488404
references.citation: Anticancer Res. 2001 Mar-Apr;21(2A):873-8
references.pmid: 11396178
references.citation: Chem Biol Interact. 2000 Aug 15;128(1):19-38
references.pmid: 10996298
references.citation: Basic Clin Pharmacol Toxicol. 2009 Mar;104(3):236-40
references.pmid: 19175364
references.citation: Phytother Res. 2004 Oct;18(10):798-804
references.pmid: 15551376