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    ABSTRACT: Phosphoinositide 3-kinases (PI3Ks) regulate several cellular functions that are critical for cancer progression and development, including cell survival, proliferation and migration. Three classes of PI3Ks exist with the class I PI3K encompassing four isoforms of the catalytic subunit known as p110α, p110β, p110γ, and p110δ. Although for many years attention has been mainly focused on p110α recent evidence supports the conclusion that p110β, p110γ, and p110δ can also have a role in cancer. Amongst these, accumulating evidence now indicates that p110γ is involved in several cellular processes associated with cancer and indeed this specific isoform has emerged as a novel important player in cancer progression. Studies from our laboratory have identified a specific overexpression of p110γ in human pancreatic ductal adenocarcinoma (PDAC) and in hepatocellular carcinoma (HCC) tissues compared to their normal counterparts. Our data have further established that selective inhibition of p110γ is able to block PDAC and HCC cell proliferation, strongly suggesting that pharmacological inhibition of this enzyme can directly affect growth of these tumors. Furthermore, increasing evidence suggests that p110γ plays also a key role in the interactions between cancer cells and tumor microenvironment and in particular in tumor-associated immune response. It has also been reported that p110γ can regulate invasion of myeloid cells into tumors and tumor angiogenesis. Finally p110γ has also been directly involved in regulation of cancer cell migration. Taken together these data indicate that p110γ plays multiple roles in regulation of several processes that are critical for tumor progression and metastasis. This review will discuss the role of p110γ in gastrointestinal tumor development and progression and how targeting this enzyme might represent a way to target very aggressive tumors such as pancreatic and liver cancer on multiple fronts.
    Frontiers in Physiology 10/2014; 5:391. DOI:10.3389/fphys.2014.00391
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    ABSTRACT: It should be noted that 3-phosphoinositide-dependent protein kinase-1 (PDK1) is a protein encoded by the PDPK1 gene, which plays a key role in the signaling pathways activated by several growth factors and hormones. PDK1 is a crucial kinase that functions downstream of phosphoinositide 3-kinase activation and activates members of the AGC family of protein kinases, such as protein kinase B (Akt), protein kinase C (PKC), p70 ribosomal protein S6 kinases, and serum glucocorticoid-dependent kinase, by phosphorylating serine/threonine residues in the activation loop. AGC kinases are known to play crucial roles in regulating physiological processes relevant to metabolism, growth, proliferation, and survival. Changes in the expression and activity of PDK1 and several AGC kinases have been linked to human diseases including cancer. Recent data have revealed that the alteration of PDK1 is a critical component of oncogenic phosphoinositide 3-kinase signaling in breast cancer, suggesting that inhibition of PDK1 can inhibit breast cancer progression. Indeed, PDK1 is highly expressed in a majority of human breast cancer cell lines and both PDK1 protein and messenger ribonucleic acid are overexpressed in a majority of human breast cancers. Furthermore, overexpression of PDK1 is sufficient to transform mammary epithelial cells. PDK1 plays an essential role in regulating cell migration, especially in the context of phosphatase and tensin homologue deficiency. More importantly, downregulation of PDK1 levels inhibits migration and experimental metastasis of human breast cancer cells. Thus, targeting PDK1 may be a valuable anticancer strategy that may improve the efficacy of chemotherapeutic strategies in breast cancer patients. In this review, we summarize the evidence that has been reported to support the idea that PDK1 may be a key target in breast cancer management.
    Cancer Management and Research 08/2013; 5:271-280. DOI:10.2147/CMAR.S35026
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    ABSTRACT: AIMS/HYPOTHESIS: Sirtuin (SIRT)3 is a mitochondrial protein deacetylase that regulates reactive oxygen species (ROS) production and exerts anti-inflammatory effects. As chronic inflammation and mitochondrial dysfunction are key factors mediating pancreatic beta cell impairment in type 2 diabetes, we investigated the role of SIRT3 in the maintenance of beta cell function and mass in type 2 diabetes. METHODS: We analysed changes in SIRT3 expression in experimental models of type 2 diabetes and in human islets isolated from type 2 diabetic patients. We also determined the effects of SIRT3 knockdown on beta cell function and mass in INS1 cells. RESULTS: SIRT3 expression was markedly decreased in islets isolated from type 2 diabetes patients, as well as in mouse islets or INS1 cells incubated with IL1β and TNFα. SIRT3 knockdown in INS1 cells resulted in lowered insulin secretion, increased beta cell apoptosis and reduced expression of key beta cell genes. SIRT3 knockdown also blocked the protective effects of nicotinamide mononucleotide on pro-inflammatory cytokines in beta cells. The deleterious effects of SIRT3 knockdown were mediated by increased levels of cellular ROS and IL1β. CONCLUSIONS/INTERPRETATION: Decreased beta cell SIRT3 levels could be a key step in the onset of beta cell dysfunction, occurring via abnormal elevation of ROS levels and amplification of beta cell IL1β synthesis. Strategies to increase the activity or levels of SIRT3 could generate attractive therapies for type 2 diabetes.
    Diabetologia 02/2013; DOI:10.1007/s00125-013-2851-y
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    ABSTRACT: It is very good news that a consensus has been reached in the UK on using HbA(1c) measurements for the diagnosis of diabetes, especially as this is a development that has taken over 30 years to develop from a twinkle in several eyes [1,2], which saw potential for these assays for diagnosis and for risk assessment, to being a methodology suitable for use worldwide. People being investigated or screened for established diabetes should no longer have to fast for an oral glucose tolerance test nor to be encouraged, paradoxically, to eat large amounts of carbohydrates for 3 days before such a test in order to avoid a false positive diagnosis of diabetes; a necessary prequel to an oral glucose tolerance test that it has never been easy to ensure. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.
    Diabetic Medicine 11/2012; 30(4). DOI:10.1111/dme.12072
  • The British journal of nutrition 11/2012; 108(11):1. DOI:10.1017/S0007114512004825
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    ABSTRACT: The last quarter of a century has witnessed remarkable progress in the understanding of phosphoinositide 3-kinases (PI3K) signalling and their involvement in different disease such as cancer, diabetes, inflammation. Nevertheless, many questions remain open and among these the role of genetic and epigenetic regulation of PI3K isoforms is one of the most prominent. Emerging evidence indicates that PI3K isoforms levels can be modulated upon stimulation or in both physiological and pathological conditions including increased gene copy number and transcription regulation. In addition, intriguing role for epigenetic regulation of PI3K expression, caused by mechanisms other than changes in the underlying DNA sequence, are starting to get appreciated. In this review, we summarize the genetic and epigenetic regulation of PI3Ks in physiology and the role played by their alterations in different diseases.
    Current pharmaceutical design 09/2012; 19(4). DOI:10.2174/13816128130408
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    ABSTRACT: This report reviews evidence on disorders related to inadequate vitamin D repletion in older people. Vitamin D is as essential for bone health in adults as in children, preventing osteomalacia and muscle weakness and protecting against falls and low-impact fractures. Vitamin D is provided by skin synthesis by UVB-irradiation from summer sunshine and to a small extent by absorption from food. However, these processes become less efficient with age. Loss of mobility or residential care restricts solar exposure. Reduced appetite and financial problems often add to these problems. Thus, hypovitaminosis D is common world-wide, but is more common and more severe in older people. Non-classical effects of vitamin D, depending on serum circulating 25-hydroxyvitamin D concentrations, are present in most non-bony tissues; disorders associated with hypovitaminosis D include increased risks of sepsis [bacterial, mycobacterial and viral], cardiovascular and metabolic disorders [e.g. hyperlipidemia, type 2 diabetes mellitus, acute vascular events, dementia, stroke and heart failure]. Many cancer risks are associated with vitamin D inadequacy, though causality is accepted only for colo-rectal cancer. Maintenance of repletion in healthy older people requires intakes of ≥800IU/day [20μg], as advised by the Institute of Medicine [IOM], but achieving such intakes usually requires supplementation. Excessive intakes are dangerous, especially in undiagnosed primary hyperparathyroidism or sarcoidosis, but the IOM finds doses <4000 IU/day are safe. Many experts suggest that ≥1000-2000 IU [25-50μg] of vitamin D daily is necessary for older people, especially when independence is lost, or hypovitaminosis D could add to the clinical problem[s]. Much higher doses than these are needed for treatment of established deficiency or insufficiency.
    Aging and Disease 08/2012; 3(4):313-29.
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    ABSTRACT: Class II isoforms of PI3K (phosphoinositide 3-kinase) are still the least investigated and characterized of all PI3Ks. In the last few years, an increased interest in these enzymes has improved our understanding of their cellular functions. However, several questions still remain unanswered on their mechanisms of activation, their specific downstream effectors and their contribution to physiological processes and pathological conditions. Emerging evidence suggests that distinct PI3Ks activate different signalling pathways, indicating that their functional roles are probably not redundant. In the present review, we discuss the recent advances in our understanding of mammalian class II PI3Ks and the evidence suggesting their involvement in human diseases.
    Biochemical Journal 05/2012; 443(3):587-601. DOI:10.1042/BJ20120008
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    ABSTRACT: INTRODUCTION: Multidrug resistance (MDR) is the main cause of failure in cancer therapy. One mechanism responsible for MDR is the active efflux of drugs by ATP-binding cassette (ABC) transporters. Several agents have been developed to block transporter-mediated drug efflux and some of these compounds have entered Phase II/III clinical testing. Evidence is also emerging of the role played by ABC transporters in cancer cell signalling that is likely to be important in disease progression and which is distinct from MDR. AREAS COVERED: This article reviews current literature to analyse the rationale for targeting ABC transporters in cancer. Preclinical and clinical results of ABC transporter inhibitors in early clinical trials, as single agents or in combination with other drugs, are described. The development of new strategies to target MDR and the emerging roles of ABC transporters in cancer signalling are discussed. EXPERT OPINION: The intense active search for safe and effective inhibitors of ABC transporters has led to some success in MDR reversal in preclinical studies. However, there has been little impact on clinical outcome. The discovery of novel, potent and nontoxic inhibitors as well as new treatment strategies is therefore needed.
    Expert Opinion on Investigational Drugs 05/2012; 21(5):657-66. DOI:10.1517/13543784.2012.679339
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    ABSTRACT: Review of the evidence on hypovitaminosis D as a risk factor for metabolic syndrome and its sequelae, T2DM and CVD, suggests long-term vitamin D repletion could reduce these risks. There is mechanistic evidence for protective effects for MetS and the balance of evidence, (cross-sectional and prospective), supports this postulate. Much of the data so far available from randomized controlled trials is weakened by inadequate power, low vitamin D dosages, starting supplementation too late in life or after MetS disorders have developed or, most importantly, by non-inclusion of many recognizable confounders. On balance, therefore, maintenance of US 2010 recommended intakes for bone protection has the potential to prove protective for MetS. Supplementation has been shown to increase survival in patients with cardiac disorders; whether higher doses would provide useful protection for apparently healthy people in the general population awaits the outcomes of ongoing randomized-controlled trials that, it is hoped, will prove or disprove causality for hypovitaminosis D in MetS and its long-term ill-effects.
    Dermato-Endocrinology 04/2012; 4(2):212-24. DOI:10.4161/derm.20012
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