Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The LKB1 tumour suppressor phosphorylates and activates AMPK (AMP-activated protein kinase) when cellular energy levels are low, thereby suppressing growth through multiple pathways, including inhibiting the mTORC1 (mammalian target of rapamycin complex 1) kinase that is activated in the majority of human cancers. Blood glucose-lowering Type 2 diabetes drugs also induce LKB1 to activate AMPK, indicating that these compounds could be used to suppress growth of tumour cells. In the present study, we investigated the importance of the LKB1-AMPK pathway in regulating tumorigenesis in mice resulting from deficiency of the PTEN (phosphatase and tensin homologue deleted on chromosome 10) tumour suppressor, which drives cell growth through overactivation of the Akt and mTOR (mammalian target of rapamycin) kinases. We demonstrate that inhibition of AMPK resulting from a hypomorphic mutation that decreases LKB1 expression does not lead to tumorigenesis on its own, but markedly accelerates tumour development in PTEN(+/-) mice. In contrast, activating the AMPK pathway by administration of metformin, phenformin or A-769662 to PTEN(+/-) mice significantly delayed tumour onset. We demonstrate that LKB1 is required for activators of AMPK to inhibit mTORC1 signalling as well as cell growth in PTEN-deficient cells. Our findings highlight, using an animal model relevant to understanding human cancer, the vital role that the LKB1-AMPK pathway plays in suppressing tumorigenesis resulting from loss of the PTEN tumour suppressor. They also suggest that pharmacological inhibition of LKB1 and/or AMPK would be undesirable, at least for the treatment of cancers in which the mTORC1 pathway is activated. Most importantly, our results demonstrate the potential of AMPK activators, such as clinically approved metformin, as anticancer agents, which will suppress tumour development by triggering a physiological signalling pathway that potently inhibits cell growth.
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PMID:Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. 1846 13

The emergence of protein-tyrosine phosphatase 1B (PTP1B) as a potential drug target for treatment of diabetes, obesity, and cancer underlies the importance of understanding its full range of cellular functions. Here, we have identified cortactin, a central regulator of actin cytoskeletal dynamics, as a substrate of PTP1B. A trapping mutant of PTP1B binds cortactin at the phosphorylation site Tyr(446), the regulation and function of which have not previously been characterized. We show that phosphorylation of cortactin Tyr(446) is induced by hyperosmolarity and potentiates apoptotic signaling during prolonged hyperosmotic stress. This study advances the importance of Tyr(446) in the regulation of cortactin and provides a potential mechanism to explain the effects of PTP1B on processes including cell adhesion, migration, and tumorigenesis.
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PMID:PTP1B regulates cortactin tyrosine phosphorylation by targeting Tyr446. 1838 54

Endogenous reactive intermediates including photoexcited states of tissue chromophores, reactive oxygen species (ROS), reactive carbonyl species (RCS), transition metal ions, and Schiff bases have been implicated in the initiation and progression of diverse human pathologies including tumorigenesis, atherosclerosis, diabetes, and neurodegenerative disease. In contrast to structure-based approaches that target macromolecules by selective ligands, reactivity-based drug discovery uses chemical reagents as therapeutics that target reactive chemical species involved in human pathology. Reactivity-based design of prototype agents that effectively antagonize, modulate, and potentially even reverse the chemistry underlying tissue damage from oxidative and carbonyl stress therefore holds great promise in delivering significant therapeutic benefit. Apart from its established role as an essential cofactor for numerous enzymes, a large body of evidence suggests that B(6)-vitamers contain reactive pharmacophores that mediate therapeutically useful non-vitamin drug actions as potent antioxidants, metal chelators, carbonyl scavengers, Schiff base forming agents, and photosensitizers. Based on the fascinating chemical versatility of B(6)-derived pharmacophores, B(6)-vitamers are therefore promising lead compounds for reactivity-based drug design.
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PMID:Reactivity-based drug discovery using vitamin B(6)-derived pharmacophores. 1847 39

The PI3K-AKT network, which is activated by cytokines or growth factors, mediates intracellular signals to regulate a variety of cellular responses, including antiapoptosis, proliferation, cell cycling, protein synthesis, glucose metabolism, and telomere activity. Genomic mutations, alterations of the PI3K-AKT regulatory network, underlie such diseases as cancer, glucose intolerance (diabetes mellitus), schizophrenia, and/or autoimmune diseases. In addition to direct tumorigenesis involvement by genetically altering human cancer, the PI3K-AKT network underlies the clinical manifestation of different stages of tumorigenic viral infection, such as latent and chronic infection, and malignant transformation of Epstein-Barr, hepatitis C, hepatitis B, and human immunodeficiency virus (HIV) viruses. We summarize updated knowledge on the PI3K-AKT network underlying different phathological viral and/or bacterial infections. Antiviral activity engendered by suppressing of PI3K-AKT activity, rather than directly targeting anticancer activity via oncogenes, may thus open up ways to prevent malignant transformation by tumorigenic viral infection.
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PMID:[PI3K-AKT network roles in infectious diseases]. 1854 44

The Rho family GTPase Cdc42 regulates cytoskeletal organization and membrane trafficking in physiological processes such as cell proliferation, motility and polarity. Aberrant activation of Cdc42 results in pathogenesis, such as tumorigenesis and tumor progression, cardiovascular diseases, diabetes, and neuronal degenerative diseases. The activation of Cdc42 in response to upstream signals is mediated by guanine nucleotide exchange factors (GEFs), which converse GDP-bound inactive form to the GTP-bound active form of Cdc42. The activated Cdc42 transduces signals to downstream effectors and generates cellular effects. This review will discuss the molecular mechanism of activation of Cdc42 and postulate that signaling specificity of Cdc42 is conferred by the GEF/GTPase/Effector (GGE) complexes in response to external stimuli.
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PMID:Cellular signaling for activation of Rho GTPase Cdc42. 1855 78

Glycogen synthase kinase 3beta (GSK3beta), a multifunctional serine/threonine kinase found in all eukaryotes, had been initially identified as a key regulator of insulin-dependent glycogen synthesis. It is now known that GSK3beta functions in diverse cellular processes including proliferation, differentiation, motility and survival. Aberrant regulation of GSK3beta has been implicated in a range of human pathologies including non-insulin-dependent diabetes mellitus, cardiovascular disease, some neurodegenerative diseases, and bipolar disorder. As a consequence, the therapeutic potential of GSK3beta inhibitors has become an important area of investigation. However, GSK3beta also participates in neoplastic transformation and tumor development. The role of GSK3beta in tumorigenesis and cancer progression remains controversial; it may function as a "tumor suppressor" for certain types of tumors, but promotes growth and development for some others. GSK3beta also mediates drug sensitivity/resistance in cancer chemotherapy. Therefore, although GSK3beta is an attractive therapeutic target for a number of human diseases, its potential impact on tumorigenesis and cancer chemotherapy needs to be carefully evaluated. This mini-review discusses the role of GSK3beta in tumorigenesis/cancer progression as well as its modulation of cancer chemotherapy.
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PMID:Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. 1860 91

Pancreatic progenitor cells represent both a potential source of transplantable islets for the treatment of diabetes and a valuable instrument for the investigation of the tumorigenesis of pancreatic carcinoma. It has been reported that pancreatic ductal cells of adults have the characteristics of pancreatic progenitors, but whether these cells can generate endocrine cells requires verification. Here, the differentiation of daughter cells of CD24(-) pancreatic ductal cells into insulin-secreting cells in vitro is reported. Crude pancreatic ductal cells were first obtained from adult mice by gradient centrifugation, and then the CD24(-) cells were isolated with a fluorescence-activated cell sorter. The isolated cells were cultured in serum-containing medium at clonal density to form epithelial colonies (ECs). The ECs were then stimulated with basic fibroblast growth factor (bFGF). After 72 h, insulin-secreting cells were observed in the ECs. These results indicate that the daughter cells of CD24(-) pancreatic ductal cells can differentiate into insulin-secreting cells in vitro when stimulated with exogenous bFGF. Therefore, CD24(-) pancreatic ductal cells have the potential to be pancreatic progenitor cells.
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PMID:Differentiation of CD24- pancreatic ductal cell-derived cells into insulin-secreting cells. 1865 67

Multiple endocrine neoplasia type 1 (MEN1), a human familial tumor syndrome, results from mutations in the Men1 gene. Although much progress has been made in demonstrating the definitive role for menin in suppressing tumorigenesis in endocrine organs, the molecular pathways responsible for menin action in normal tissues and tumors remain poorly defined. Here, we review the recent progress on the molecular functions of menin in controlling cell proliferation, apoptosis, and DNA repair. The majority of these functions are largely executed by menin-mediated influencing of histone modifications and chromatin structure. These findings lead to a new model of understanding menin's tumor-suppressing function, providing insights into understanding of how menin regulates cell proliferation and the development of endocrine tumors. The new knowledge could also be translated into new strategies to improve therapeutic interventions against MEN1 and other endocrine diseases including diabetes.
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PMID:Menin regulates endocrine diseases by controlling histone modification and gene transcription. 1875 93

Despite diversity in genetic events in oncogenesis, cancer cells exhibit a common set of functional characteristics. Otto Warburg discovered that cancer cells have consistently higher rates of glycolysis than normal cells. The underlying mechanisms leading to the Warburg phenomenon include mitochondrial changes, upregulation of rate-limiting enzymes/proteins in glycolysis and intracellular pH regulation, hypoxia-induced switch to anaerobic metabolism, and metabolic reprogramming after loss of p53 function. The regulation of energy metabolism can be traced to a "triad" of transcription factors: c-MYC, HIF-1 and p53. Oncogenetic changes involve a nonrandom set of gene deletions, amplifications and mutations, and many oncogenes and tumor suppressor genes cluster along the signaling pathways that regulate c-MYC, HIF-1 and p53. Glycolysis in cancer cells has clinical implications in cancer diagnosis, treatment and interaction with diabetes mellitus. Many drugs targeting energy metabolism are in development. Future advances in technology may bring about transcriptome and metabolome-guided chemotherapy.
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PMID:Roles of p53, MYC and HIF-1 in regulating glycolysis - the seventh hallmark of cancer. 1876 98

Curcumin, a yellow pigment present in the Indian spice turmeric (associated with curry powder), has been linked with suppression of inflammation; angiogenesis; tumorigenesis; diabetes; diseases of the cardiovascular, pulmonary, and neurological systems, of skin, and of liver; loss of bone and muscle; depression; chronic fatigue; and neuropathic pain. The utility of curcumin is limited by its color, lack of water solubility, and relatively low in vivo bioavailability. Because of the multiple therapeutic activities attributed to curcumin, however, there is an intense search for a "super curcumin" without these problems. Multiple approaches are being sought to overcome these limitations. These include discovery of natural curcumin analogues from turmeric; discovery of natural curcumin analogues made by Mother Nature; synthesis of "man-made" curcumin analogues; reformulation of curcumin with various oils and with inhibitors of metabolism (e.g., piperine); development of liposomal and nanoparticle formulations of curcumin; conjugation of curcumin prodrugs; and linking curcumin with polyethylene glycol. Curcumin is a homodimer of feruloylmethane containing a methoxy group and a hydroxyl group, a heptadiene with two Michael acceptors, and an alpha,beta-diketone. Structural homologues involving modification of all these groups are being considered. This review focuses on the status of all these approaches in generating a "super curcumin.".
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PMID:Biological activities of curcumin and its analogues (Congeners) made by man and Mother Nature. 1877 80


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