title: SIRT1 and circadian gene expression in pancreatic ductal adenocarcinoma: Effect of starvation.
abstract: Pancreatic cancer (PC), the fourth leading cause of cancer-related deaths, is characterized by high aggressiveness and resistance to chemotherapy. Pancreatic carcinogenesis is kept going by derangement of essential cell processes, such as proliferation, apoptosis, metabolism and autophagy, characterized by rhythmic variations with 24-h periodicity driven by the biological clock. We assessed the expression of the circadian genes ARNLT, ARNLT2, CLOCK, PER1, PER2, PER3, CRY1, CRY2 and the starvation-activated histone/protein deacetylase SIRT1 in 34 matched tumor and non-tumor tissue specimens of PC patients, and evaluated in PC derived cell lines if the modulation of SIRT1 expression through starvation could influence the temporal pattern of expression of the circadian genes. We found a significant down-regulation of ARNLT (p = 0.015), CRY1 (p = 0.013), CRY2 (p = 0.001), PER1 (p < 0.0001), PER2 (p < 0.001), PER3 (p = 0.001) and SIRT1 (p = 0.017) in PC specimens. PER3 and CRY2 expression levels were lower in patients with jaundice at diagnosis ( < 0.05). Having adjusted for age, adjuvant therapy and tumor stage, we evidenced that patients with higher PER2 and lower SIRT1 expression levels showed lower mortality (p = 0.028). Levels and temporal patterns of expression of many circadian genes and SIRT1 significantly changed upon serum starvation in vitro, with differences among four different PC cell lines examined (BXPC3, CFPAC, MIA-PaCa-2 and PANC-1). Serum deprivation induced changes of the overall mean level of the wave and amplitude, lengthened or shortened the cycle time and phase-advanced or phase-delayed the rhythmic oscillation depending on the gene and the PC cell line examined. In conclusion, a severe deregulation of expression of SIRT1 and circadian genes was evidenced in the cancer specimens of PC patients, and starvation influenced gene expression in PC cell lines, suggesting that the altered interplay between SIRT1 and the core circadian proteins could represent a crucial player in the process of pancreatic carcinogenesis.
authors: Division of Gastroenterology, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza" , San Giovanni Rotondo (FG) , Italy .
authors: Francesca
authors: F
authors: Tavano
authors: Valerio
authors: V
authors: Pazienza
authors: Andrea
authors: A
authors: Fontana
authors: Francesca Paola
authors: FP
authors: Burbaci
authors: Concita
authors: C
authors: Panebianco
authors: Chiara
authors: C
authors: Saracino
authors: Lucia
authors: L
authors: Lombardi
authors: Antonio
authors: A
authors: De Bonis
authors: Fabio Francesco
authors: FF
authors: di Mola
authors: Pierluigi
authors: P
authors: di Sebastiano
authors: Ada
authors: A
authors: Piepoli
authors: Manlio
authors: M
authors: Vinciguerra
authors: Massimo
authors: M
authors: Fracavilla
authors: Francesco
authors: F
authors: Giuliani
authors: Rosa
authors: R
authors: Rubino
authors: Angelo
authors: A
authors: Andriulli
authors: Gianluigi
authors: G
authors: Mazzoccoli
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000368:Aged; D056926:CLOCK Proteins / Q000235:genetics* / Q000378:metabolism; D002940:Circadian Rhythm / Q000235:genetics* / Q000502:physiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000235:genetics*; D056564:Sirtuin 1 / Q000235:genetics*
chemical_list: D056926:CLOCK Proteins; C447939:SIRT1 protein, human; D056564:Sirtuin 1
keywords: Cancer; SIRT1; circadian; clock gene; pancreas; rhythm