A group of genetic diseases known as polycystic liver disease (PLD) are distinguished by the gradual development of fluid-filled hepatic cysts formed from cholangiocytes and commonly related to ...primary cilia defects. The NAD salvage pathway, which sustains cellular bioenergetics and supplies a required substrate for tasks important to rapidly multiplying cells, has a rate-limiting phase that is mediated by nicotinamide phosphoribosyltransferase (NAMPT). In this study, the efficacy and mechanisms of action of FK866, a novel, high-potency NAMPT inhibitor with a good toxicity profile, were assessed. NAMPT-siRNA and FK866 reduced NAD levels and inhibited the proliferation of PLD cells in a dose-dependent manner. Notably, this pharmacologic and siRNA-mediated suppression of NAMPT was less effective in normal cells at the same concentrations. The addition of nicotinamide mononucleotide (NMN), a byproduct of NAMPT that restores NAD concentration, rescued the cellular viability of PLD cells and verified the on-target action of FK866. In FK866-treated PLD cells, mitochondrial respiration and ATP production were impaired and reactive oxygen species production was induced. Importantly, FK866 treatment was associated with improved effects of octreotide, a drug used for PLD treatment. As a result, the use of NAMPT inhibitors, including FK866 therapy, offers the possibility of a further targeted strategy for the therapeutic treatment of PLD.
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The primary cilium is an organelle that nearly all cells within the body contain. Its function is to sense the extracellular environment through its abundance of receptors and linked ...signaling pathways, working as an antenna. Ciliary defects lead to different pathologies. In particular, many tumors lose primary cilia, and this is linked with negative implications for the cell such as an increase in malignancy. In this work we will go through the knowledge of the role of primary cilia in normal conditions, how it is involved in diverse signaling pathways, and in disease, particularly in cancer, highlighting its tumor suppressor properties.
The cholangiocyte primary cilium in health and disease Mansini, Adrian P.; Peixoto, Estanislao; Thelen, Kristen M. ...
Biochimica et biophysica acta. Molecular basis of disease,
04/2018, Letnik:
1864, Številka:
4
Journal Article
Recenzirano
Odprti dostop
Cholangiocytes, like most cells, express primary cilia extending from their membranes. These organelles function as antennae which detect stimuli from bile and transmit the information into cells ...regulating several signaling pathways involved in secretion, proliferation and apoptosis. The ability of primary cilia to detect different signals is provided by ciliary associated proteins which are expressed in its membrane. Defects in the structure and/or function of these organelles lead to cholangiociliopathies that result in cholangiocyte hyperproliferation, altered fluid secretion and absorption. Since primary cilia dysfunction has been observed in several epithelial tumors, including cholangiocarcinoma (CCA), primary cilia have been proposed as tumor suppressor organelles. In addition, the loss of cilia is associated with dysregulation of several molecular pathways resulting in CCA development and progression. Thus, restoration of the primary cilia may be a potential therapeutic approach for several ciliopathies and CCA.
Primary cilia are multisensory organelles recently found to be absent in some tumor cells, but the mechanisms of deciliation and the role of cilia in tumor biology remain unclear. Cholangiocytes, the ...epithelial cells lining the biliary tree, normally express primary cilia and their interaction with bile components regulates multiple processes, including proliferation and transport. Using cholangiocarcinoma as a model, we found that primary cilia are reduced in cholangiocarcinoma by a mechanism involving histone deacetylase 6 (HDAC6). The experimental deciliation of normal cholangiocyte cells increased the proliferation rate and induced anchorage-independent growth. Furthermore, deciliation induced the activation of mitogen-activated protein kinase and Hedgehog signaling, two important pathways involved in cholangiocarcinoma development. We found that HDAC6 is overexpressed in cholangiocarcinoma and overexpression of HDAC6 in normal cholangiocytes induced deciliation and increased both proliferation and anchorage-independent growth. To evaluate the effect of cilia restoration on tumor cells, we targeted HDAC6 by short hairpin RNA (shRNA) or by the pharmacologic inhibitor, tubastatin-A. Both approaches restored the expression of primary cilia in cholangiocarcinoma cell lines and decreased cell proliferation and anchorage-independent growth. The effects of tubastatin-A were abolished when cholangiocarcinoma cells were rendered unable to regenerate cilia by stable transfection of IFT88-shRNA. Finally, inhibition of HDAC6 by tubastatin-A also induced a significant decrease in tumor growth in a cholangiocarcinoma animal model. Our data support a key role for primary cilia in malignant transformation, provide a plausible mechanism for their involvement, and suggest that restoration of primary cilia in tumor cells by HDAC6 targeting may be a potential therapeutic approach for cholangiocarcinoma.
Hepatobiliary cancers comprise a wide range of malignancies such as hepatocellular carcinoma and cholangiocarcinoma, and they are some of the most challenging to treat human neoplasms. Due to the ...rarity of the illnesses, the development of treatment measures for malignancies of the gastrointestinal system is far behind. The number of patients eligible for curative treatment is limited due to cancer's aggressive nature and the difficulties of early identification. Furthermore, surgery is frequently intrusive and linked with a significant level of risk. The therapy result of hepatobiliary cancers is unsatisfactory due to these complicated variables, leaving significant space for improvement.
Cholangiocytes, the epithelial cells lining the biliary tree in the liver, express primary cilia that can detect several kinds of environmental signals and then transmit this information into the ...cell. We have reported that cilia are significantly reduced in cholangiocarcinoma (CCA) and that the experimental deciliation of normal cells induces a malignant‐like phenotype with increased proliferation, anchorage‐independent growth, invasion, and migration. Here, we tested the hypothesis that the chemosensory function of cholangiocyte primary cilia acts as a mechanism for tumor suppression. We found that in the presence of extracellular nucleotides cilia‐dependent chemosensation of the nucleotides inhibited migration and invasion in normal ciliated cholangiocytes through a P2Y11 receptor and liver kinase B1 (LKB1)–phosphatase and tensin homolog–AKT–dependent mechanism. In contrast, in normal deciliated cholangiocytes and CCA cells, the nucleotides induced the opposite effects, i.e., increased migration and invasion. As activation of LKB1 through a cilia‐dependent mechanism was required for the nucleotide‐mediated inhibitory effects on migration and invasion, we attempted to activate LKB1 directly, independent of ciliary expression, using the compound hesperidin methyl chalcone (HMC). We found that HMC induced activation of LKB1 in both ciliated and deciliated cells in vitro, resulting in the inhibition of migration and proliferation. Furthermore, using a rat syngeneic orthotopic CCA model, we found that HMC inhibited tumor growth in vivo. Conclusion: These findings highlight the importance of the chemosensory function of primary cilia for the control of migration and invasion and suggest that, by directly activating LKB1 and bypassing the need for primary cilia, it is possible to emulate this chemosensory function in CCA cells; these data warrant further studies evaluating the possibility of using HMC as therapy for CCA.
Cholangiocarcinoma (CCA) is a highly invasive and metastatic form of carcinoma with bleak prognosis due to limited therapies, frequent relapse, and chemotherapy resistance. There is an urgent need to ...identify the molecular regulators of CCA in order to develop novel therapeutics and advance diseases diagnosis. Many cellular proteins including histones may undergo a series of enzyme-mediated post-translational modifications including acetylation, methylation, phosphorylation, sumoylation, and crotonylation. Histone deacetylases (HDACs) play an important role in regulating epigenetic maintenance and modifications of their targets, which in turn exert critical impacts on chromatin structure, gene expression, and stability of proteins. As such, HDACs constitute a group of potential therapeutic targets for CCA. The aim of this review was to summarize the role that HDACs perform in regulating epigenetic changes, tumor development, and their potential as therapeutic targets for CCA.
Cilia are microtubule-based organelles that project from the cell surface with motility or sensory functions. Primary cilia work as antennae to sense and transduce extracellular signals. Cilia ...critically control proliferation by mediating cell-extrinsic signals and by regulating cell cycle entry. Recent studies have shown that primary cilia and their associated proteins also function in autophagy and genome stability, which are important players in oncogenesis. Abnormal functions of primary cilia may contribute to oncogenesis. Indeed, defective cilia can either promote or suppress cancers, depending on the cancer-initiating mutation, and the presence or absence of primary cilia is associated with specific cancer types. Together, these findings suggest that primary cilia play important, but distinct roles in different cancer types, opening up a completely new avenue of research to understand the biology and treatment of cancers. In this review, we discuss the roles of primary cilia in promoting or inhibiting oncogenesis based on the known or predicted functions of cilia and cilia-associated proteins in several key processes and related clinical implications.
The short-chain fatty acid butyrate, produced from fermentable carbohydrates by gut microbiota in the colon, has multiple beneficial effects on human health. At the intestinal level, butyrate ...regulates metabolism, helps in the transepithelial transport of fluids, inhibits inflammation, and induces the epithelial defense barrier. The liver receives a large amount of short-chain fatty acids via the blood flowing from the gut via the portal vein. Butyrate helps prevent nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, inflammation, cancer, and liver injuries. It ameliorates metabolic diseases, including insulin resistance and obesity, and plays a direct role in preventing fatty liver diseases. Butyrate has different mechanisms of action, including strong regulatory effects on the expression of many genes by inhibiting the histone deacetylases and modulating cellular metabolism. The present review highlights the wide range of beneficial therapeutic and unfavorable adverse effects of butyrate, with a high potential for clinically important uses in several liver diseases.
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