title: The NAD+-dependent histone deacetylase SIRT6 promotes cytokine production and migration in pancreatic cancer cells by regulating Ca2+ responses.
abstract: Cytokine secretion by cancer cells contributes to cancer-induced symptoms and angiogenesis. Studies show that the sirtuin SIRT6 promotes inflammation by enhancing TNF expression. Here, we aimed to determine whether SIRT6 is involved in conferring an inflammatory phenotype to cancer cells and to define the mechanisms linking SIRT6 to inflammation. We show that SIRT6 enhances the expression of pro-inflammatory cyto-/chemokines, such as IL8 and TNF, and promotes cell migration in pancreatic cancer cells by enhancing Ca(2+) responses. Via its enzymatic activity, SIRT6 increases the intracellular levels of ADP-ribose, an activator of the Ca(2+) channel TRPM2. In turn, TRPM2 and Ca(2+) are shown to be involved in SIRT6-induced TNF and IL8 expression. SIRT6 increases the nuclear levels of the Ca(2+)-dependent transcription factor, nuclear factor of activated T cells (NFAT), and cyclosporin A, a calcineurin inhibitor that reduces NFAT activity, reduces TNF and IL8 expression in SIRT6-overexpressing cells. These results implicate a role for SIRT6 in the synthesis of Ca(2+)-mobilizing second messengers, in the regulation of Ca(2+)-dependent transcription factors, and in the expression of pro-inflammatory, pro-angiogenic, and chemotactic cytokines. SIRT6 inhibition may help combat cancer-induced inflammation, angiogenesis, and metastasis.
authors.affiliation: Department of Internal Medicine, Section of Biochemistry and Center of Excellence for Biomedical Research (CEBR), University of Genoa, 16132 Genoa, Italy.
authors.forename: Inga
authors.initials: I
authors.lastname: Bauer
authors.forename: Alessia
authors.initials: A
authors.lastname: Grozio
authors.forename: Denise
authors.initials: D
authors.lastname: Lasigliè
authors.forename: Giovanna
authors.initials: G
authors.lastname: Basile
authors.forename: Laura
authors.initials: L
authors.lastname: Sturla
authors.forename: Mirko
authors.initials: M
authors.lastname: Magnone
authors.forename: Giovanna
authors.initials: G
authors.lastname: Sociali
authors.forename: Debora
authors.initials: D
authors.lastname: Soncini
authors.forename: Irene
authors.initials: I
authors.lastname: Caffa
authors.forename: Alessandro
authors.initials: A
authors.lastname: Poggi
authors.forename: Gabriele
authors.initials: G
authors.lastname: Zoppoli
authors.forename: Michele
authors.initials: M
authors.lastname: Cea
authors.forename: Georg
authors.initials: G
authors.lastname: Feldmann
authors.forename: Raul
authors.initials: R
authors.lastname: Mostoslavsky
authors.forename: Alberto
authors.initials: A
authors.lastname: Ballestrero
authors.forename: Franco
authors.initials: F
authors.lastname: Patrone
authors.forename: Santina
authors.initials: S
authors.lastname: Bruzzone
authors.forename: Alessio
authors.initials: A
authors.lastname: Nencioni
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D016207:Cytokines / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D007249:Inflammation; D016209:Interleukin-8 / Q000378:metabolism; D051379:Mice; D009243:NAD / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D012190:Retroviridae / Q000378:metabolism; D015398:Signal Transduction; D037761:Sirtuins / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D016207:Cytokines; D016209:Interleukin-8; D016328:NF-kappa B; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D009243:NAD; C501860:Sirt6 protein, mouse; C516592:SIRT6 protein, human; D037761:Sirtuins; D006655:Histone Deacetylases; D002118:Calcium