The NAD+-dependent Histone Deacetylase SIRT6 Promotes Cytokine Production and Migration in Pancreatic Cancer Cells by Regulating Ca2+ Responses

Abstract

Background:Cytokine secretion has unwanted consequences in malignant and in inflammatory disorders. The deacetylase SIRT6 has pro-inflammatory activity, but the underlying mechanisms and its biological significance remain unclear. The relationship between inflammation and carcinogenesis has been known for many years (1). Chronic inflammation is a risk factor for cancer development. In addition, even in those cancers that do not develop in inflamed tissues, an inflammatory component is usually observed, and it is now known to be an essential part of the malignant microenvironment (2, 3). Inflammation contributes to tumorigenesis and cancer progression by supplying growth factors that sustain cancer cell proliferation and/or survival, proangiogenic factors, extracellular matrix-modifying enzymes that promote invasion and metastasis, and signals that lead to epithelial-mesenchymal transition (2, 4, 5). Moreover, increased circulating levels of pro-inflammatory cytokines are responsible for systemic manifestations of disease, such as cachexia, fever, and sweats (6 -9). Among other forms of cancer, pancreatic ductal adenocarcinoma (PDAC) 2 is well known for its propensity to secrete high levels of pro-inflammatory factors that contribute to its clinical aggressiveness and to its metastatic potential (10). The mechanisms controlling cyto-/chemokine production by inflammatory and cancer cells are only partially understood. A more detailed understanding of the molecular pathways leading to cancer-associated inflammation may lead to new therapeutic strategies with a strong impact on patient quality of life.Previous studies showed that intracellular nicotinamide adenine dinucleotide (NAD ϩ ) levels influence the capacity of inflammatory cells to secrete cytokines, such as tumor necrosis factor ␣ (TNF), interleukin 6 (IL6), IL1␤, interferon ␥ (IFN-␥), * This work was supported in part by the Associazione Italiana per la Ricerca sul Cancro (AIRC, Code 6108) (to A. N.), by the European Seventh Framework Program (Project 256986, PANACREAS) (to A. N.), by Ministero della Salute Grant GR-2008-1135635 (to A. N.)

The world of protein acetylation

“…Other studies have for example found that SIRT6 increases the expression of cytokines which contribute to inflammation, and to enhance the migratory ability of pancreatic cancer cells [436].…”

Astragaloside IV sensitizes non–small cell lung cancer cells to gefitinib potentially via regulation of SIRT6

“…16,17 Moreover, multiple investigations have revealed that SIRT6 regulates the pathogenesis of various types of cancers, such as including hepatocellular carcinoma, breast cancer, and pancreatic cancer. [18][19][20] Molecular mechanism exploration further indicates that the diverse roles of SIRT6 in carcinogenesis are implemented through the regulation of cellular signals including ERK, Smad, and Raf/mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase pathway. 18,21 A recent study demonstrated that overexpression of SIRT6 induced a radiosensitization effect on NSCLC cells, resulting in decreased cell growth, cell cycle arrest, and induction of cell apoptosis.…”

Quinazolinedione SIRT6 inhibitors sensitize cancer cells to chemotherapeutics

“…Finally, SIRT6 also up-regulates the expression of cytokines promoting inflammation, angiogenesis, and cachexia. This is the case of TNF-a [7e9], but also of IL-8, whose production is favored by SIRT6 via its ability to increase intracellular ADP-ribose levels, consequently promoting Ca 2þ signalling and NFAT activity [18]. Thus, based on these studies, SIRT6 inhibitors could find application in cancer treatment by targeting several aspects of cancer pathophysiology and contributing to enhance the efficacy of currently available therapeutics.…”