title: Docosahexaenoic acid reverts resistance to UV-induced apoptosis in human keratinocytes: involvement of COX-2 and HuR.
abstract: The dramatic increase in the incidence of nonmelanoma skin cancer over the last decades has been related to the augmented exposure to ultraviolet (UV) radiation (UVR). It is known that apoptosis is induced as a protective mechanism after the acute irradiation of keratinocytes, whereas apoptotic resistance and carcinogenesis may follow the chronic exposure to UVR. We found that not all the human keratinocytes lines studied underwent apoptosis following acute exposure to UVR (10-60 mJ/cm(2)). Whereas UVR induced apoptosis in the HaCaT cells, NCTC 2544 and nr-HaCaT cells showed apoptosis resistance. The cytokeratin pattern of the apoptosis-resistant cells indicated that they possessed a degree of differentiation lower than that of HaCaT cells. They also showed an enhanced expression of cyclooxygenase-2 (COX-2), an early marker of carcinogenesis in various tissues, including skin. n-3 polyunsaturated fatty acids have drawn increasing interest as nutritional factors with the potential to reduce UVR carcinogenesis, and since they are apoptosis inducers and COX-2 inhibitors in cancer cells, we investigated the ability of n-3 polyunsaturated fatty acids to influence the resistance to UVR-induced apoptosis in keratinocytes. We observed that docosahexaenoic acid (DHA) reverted the resistance of nr-HaCaT cells to UVR-induced apoptosis, increasing the Bax/Bcl-2 ratio and caspase-3 activity, and reduced COX-2 levels by inhibiting the expression of the human antigen R (HuR), a known COX-2 mRNA stabilizer in keratinocytes. The transfection of nr-HaCaT cells with HuR siRNA mimicked the proapoptotic effect of DHA. Overall, our findings further support the role of DHA as a suitable anticarcinogenic factor against nonmelanoma skin cancers.
authors.affiliation: Institute of General Pathology, School of Medicine, Catholic University, 1 - 00168 Rome, Italy.
authors.forename: Simona
authors.initials: S
authors.lastname: Serini
authors.forename: Valentina
authors.initials: V
authors.lastname: Donato
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Piccioni
authors.forename: Sonia
authors.initials: S
authors.lastname: Trombino
authors.forename: Giovanni
authors.initials: G
authors.lastname: Monego
authors.forename: Amelia
authors.initials: A
authors.lastname: Toesca
authors.forename: Idanna
authors.initials: I
authors.lastname: Innocenti
authors.forename: Mauro
authors.initials: M
authors.lastname: Missori
authors.forename: Marco
authors.initials: M
authors.lastname: De Spirito
authors.forename: Leonardo
authors.initials: L
authors.lastname: Celleno
authors.forename: Elena
authors.initials: E
authors.lastname: Fasano
authors.forename: Franco O
authors.initials: FO
authors.lastname: Ranelletti
authors.forename: Gabriella
authors.initials: G
authors.lastname: Calviello
mesh_terms: D017209:Apoptosis; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D004281:Docosahexaenoic Acids / Q000494:pharmacology*; D051959:ELAV Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects; D012333:RNA, Messenger / Q000378:metabolism; D014162:Transfection; D014466:Ultraviolet Rays / Q000009:adverse effects*; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D051959:ELAV Proteins; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; D004281:Docosahexaenoic Acids; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human