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  • Conclusions br Acknowledgements The study was supported by a


    Acknowledgements The study was supported by a grant from the Argentine National Agency for the Promotion of Science and Technology (ANPCyT) (PICT 2012-2649). N.R.S., H.H.O., G.J.H. and F.R. are research career members and N.C.G., E.A., E. H., F.M.R., are fellows of the National Scientific Research Council (CONICET, Argentina). We are grateful to the staff of the Area of Large Animals of the Animal Health Hospital of the Facultad de Ciencias Veterinarias de la Universidad Nacional del Litoral for the animal care and help with the collection of samples. We also thank DVM José Bertoli and DVM Fabián Barberis for the assistance with animal care, the staff members of the Laboratorio de Biología Celular y Molecular Aplicada (ICIVET-Litoral, UNL CONICET) for their technical support during processing of the slides, and Novartis Laboratories for the provision of drugs.
    Introduction Protein kinase C (PKC) is a prototypical class of serine/threonine kinases and influences a variety of cellular events such as cell proliferation, cell cycle, differentiation, survival, migration, and polarity [1], [2], [3]. PKC was originally identified as a cellular receptor for the phorbol ester tumor promoters more than 30 years ago [4], and at least 10 isoforms were classified into 3 major groups: conventional (cPKCs: α, βI, βII and γ), novel (nPKCs: δ, ε,η, θ and μ), and atypical (aPKCζ and λ/ι) isoforms [5]. PKCζ belongs to aPKC isozymes which are structurally and functionally distinct from other PKCs, and its catalytic activity does not require diacylglycerol, pseudosubstrate, or calcium, and also it does not serve as cellular receptors for phorbol esters [6], [7], [8]. PKCζ is critical for cell survival signaling, presumably due to its role as a downstream antimalaria medication of phosphoinositide 3-kinase (PI3K) [9]. The expression change of PKCζ has been reported in several human cancers [10], [11], [12], [13], [14]. PKCζ-deficient mice display increased Ras-induced lung carcinogenesis, showing the role of PKCζ as a tumor suppressor in vivo [13]. A proapoptotic function for PKCζ has been described in several cancer models including colorectal cancer. For example, PKCζ exhibited a proapoptotic function in ovarian cancer [15]. Also, PKCζ is reported to inhibit growth and promote differentiation and apoptosis in Caco-2 colon cancer cells. The inhibitory effect of PKCζ on the transformed phenotype of these cells indicates that downregulation of PKCζ may contribute to colon tumorigenesis [16]. There are several reports, however, highlighting a prosurvival role for PKCζ [17], [18], [19], [20]. For example, PKCζ mediates chemotaxis by regulating actin polymerization and cell adhesion, and downregulation of PKCζ expression inhibits chemotaxis signal transduction in human lung cancer cells [17]. Luna-UIIoa et al. show that the PKCζ stably depleted cells exhibited diminished tumorigenic activity in grafted mice. PKCζ activity regulates the nuclear localization of β-catenin and plays an important role in the positive regulation of canonical Wnt pathway [18]. PKCζ was reported to link multiple cellular processes of cancer, including cancer cells proliferation, cell cycle progression, tumorigenesis, promotion, invasion, and metastasis. However, the fuction of PKCζ on cancer metabolism especially in lipid metabolism is seldom mentioned and needs further exploration in detail. SIRT6, a chromatin regulatory protein, is one member of the mammalian sirtuins family of NAD+-dependent deacetylases with multiple functions in aging, metabolism, and diseases [21]. It is a critical regulator of diverse cellular processes such as transcription, genome stability, DNA repair, telomere integrity, inflammation, and metabolism [22], [23], [24], [25]. SIRT6 is also involved in regulating many aspects of cellular metabolism including lipid homeostasis. SIRT6-overexpressing mice fed a high-fat diet exhibit decreased visceral fat accumulation, improved blood lipid profile, glucose tolerance, and insulin secretion, indicating that SIRT6 can dramatically affect lipid homeostasis[26]. Kim et al. show that liver-specific deletion of SIRT6 in mice causes profound alterations in gene expression, leads to increased glycolysis and triglyceride synthesis, reduces fatty acid β-oxidation, and accelerates fatty liver formation [27]. SIRT6 and miR-122 negatively regulate each other’s expression to mediate fatty acid β-oxidation [28]. Also, a muscle-specific SIRT6 knockout mouse model shows the decreased expression of genes involved in glucose and lipid uptake, fatty acid β-oxidation, and mitochondrial oxidative phosphorylation in muscle cells through activation of AMP-activated protein kinase [29]. Despite these cumulative data, the challenge remains to explore the mechanism of SIRT6 on fatty acid β-oxidation.