Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0178874 (tumor progression)
40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The relationship between cell proliferation and the rates of glycolysis and oxidative phosphorylation in HeLa (human) and AS-30D (rodent) tumor cells was evaluated. In glutamine plus glucose medium, both tumor lines grew optimally. Mitochondria were the predominant source of ATP in both cell types (66-75%), despite an active glycolysis. In glucose-free medium with glutamine, proliferation of both lines diminished by 30% but oxidative phosphorylation and the cytosolic ATP level increased by 50%. In glutamine-free medium with glucose, proliferation, oxidative phosphorylation and ATP concentration diminished drastically, although the cells were viable. Oligomycin, in medium with glutamine plus glucose, abolished growth of both tumor lines, indicating an essential role of mitochondrial ATP for tumor progression. The presumed mitochondrial inhibitors rhodamines 123 and 6G, and casiopeina II-gly, inhibited tumor cell proliferation and oxidative phosphorylation, but also glycolysis. In contrast, gossypol, iodoacetate and arsenite strongly blocked glycolysis; however, they did not affect tumor proliferation or mitochondrial metabolism. Growth of both tumor lines was highly sensitive to rhodamines and casiopeina II-gly, with IC(50) values for HeLa cells lower than 0.5 microM, whereas viability and proliferation of human lymphocytes were not affected by these drugs (IC(50) > 30 microM). Moreover, rhodamine 6G and casiopeina II-gly, at micromolar doses, prolonged the survival of animals bearing i.p. implanted AS-30D hepatoma. It is concluded that fast-growing tumor cells have a predominantly oxidative type of metabolism, which might be a potential therapeutic target.
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PMID:Control of cellular proliferation by modulation of oxidative phosphorylation in human and rodent fast-growing tumor cells. 1658 38

Hypoxia-inducible factor (HIF)-1alpha, a global regulator of oxygen homeostasis, plays a crucial role in tumor cell adaptation to the hypoxic microenvironment through transcriptional regulation of its target genes. These genes in turn are involved in a plethora of biochemical as well as cell biological processes, including glucose metabolism, apoptosis and angiogenesis. In melanoma, HIF-1alpha has been implicated in tumor progression with effects upon metastasis and angiogenesis. However, its role in malignant transformation by oncogenes has not been described. Bedogni et al. (Cancer Cell 2005, 8:443-54) report that the hypoxic microenvironment in the skin contributes to melanocyte transformation and tumor growth induced by oncogenes Ras and Akt, which are frequently activated in melanoma. HIF-1alpha activity was found to be required in Akt-induced melanocyte transformation and tumor growth and it was suppressed greatly by mTOR inhibition with rapamycin. Since mTOR regulates HIF-1alpha expression and its transcriptional activity, rapamycin was proposed as a promising hypoxia-related therapeutic approach in melanoma treatment. This study sheds light upon the role of HIF-1alpha in the early stage of melanoma development and highlights the importance of the Akt-mTOR pathway in the regulation of HIF-1alpha.
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PMID:Hypoxic microenvironment as a cradle for melanoma development and progression. 1662 74

Recent progress in understanding the role of the tumor microenvironment in cancer progression was the subject of the 2nd International Tumor Metabolism Summit entitled "Exploiting the Tumor Microenvironment for Therapeutics," a meeting held at Palazzo Ducale in Genoa, Italy, October 7 to 8, 2005. One of the major conceptual advances in oncology over the last decade has been the appreciation that all major aspects of cancer biology are influenced by the tumor microenvironment. Two important means by which cancer cells adapt to their microenvironment are by reprogramming cellular glucose/energy metabolism to use pathways that generate ATP in the absence of O(2) and by stimulating angiogenesis to increase O(2) delivery. These responses are principally mediated at the transcriptional level by hypoxia-inducible factor-1. This meeting emphasized the complexity of the tumor microenvironment and opportunities for therapeutic intervention by targeting transcriptional and metabolic pathways that are activated during cancer progression. A better understanding of the crosstalk between signaling pathways and metabolic alterations that contribute to the cancer phenotype may provide insights leading to the development of novel therapeutic strategies.
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PMID:Meeting report: exploiting the tumor microenvironment for therapeutics. 1665 4

Epidemiological and experimental animal data indicate that exposure to both metals and metalloid species exacerbates the risk of human diseases, particularly cancers. Vascular endothelial growth factor (VEGF), which performs a primary function in both tumor progression and angiogenesis, is up-regulated due to exposure to an array of carcinogenic metals, but the mechanisms responsible for the metal activation remain somewhat poorly understood. Recently, we demonstrated that AMP-activated protein kinase (AMPK), which acts as an energy sensor, providing metabolic adaptation effects under ATP-deprived conditions, is critical for the expression of VEGF under oxygen- and glucose-deprived conditions. As carcinogenic metals are potent VEGF expression inducers, we hypothesized that AMPK would also play a crucial role in metal-induced VEGF expression. Here, we present evidence that carcinogenic metals such as arsenite, vanadate, and cobalt, induce AMPK activation and VEGF expression via several different mechanisms, and that AMPK is able to regulate the expression of VEGF mRNA in a hypoxia-inducible factor-1-dependent or -independent manner, depending on the metal applied. We also attempted to characterize the relevant signal transduction pathways in metal-induced VEGF expression and AMPK activation, as well as the role of reactive oxygen species within this context. Overall, our data suggest that AMPK is a critical regulatory component in metal-induced VEGF expression, which further implies its intrinsic involvement in metal-induced carcinogenesis.
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PMID:Critical roles of AMP-activated protein kinase in the carcinogenic metal-induced expression of VEGF and HIF-1 proteins in DU145 prostate carcinoma. 1667

Overexpression of hypoxia-inducible factors (HIF), HIF-1alpha and HIF-2alpha, leads to the up-regulation of genes involved in proliferation, angiogenesis, and glucose metabolism and is associated with tumor progression in several cancers. However, the contribution of HIF-1alpha versus HIF-2alpha to vascular endothelial growth factor (VEGF) expression and other HIF-regulated target genes under different conditions is unclear. To address this, we used small interfering RNA (siRNA) techniques to knockdown HIF-1alpha and/or HIF-2alpha expression in response to hypoxia, insulin-like growth factor (IGF)-I, or renal carcinoma cells expressing constitutively high basal levels of HIF-1alpha and/or HIF-2alpha due to loss of von Hippel-Lindau (VHL) function. We found that HIF-1alpha primarily regulates transcriptional activation of VEGF in response to hypoxia and IGF-I compared with HIF-2alpha in MCF-7 cells. We also observed a reciprocal relationship between HIF-1alpha and HIF-2alpha expression in hypoxia in these cells: HIF-2alpha siRNA enhanced HIF-1alpha-mediated VEGF expression in MCF-7 cells in response to hypoxia, which could be completely blocked by cotransfection with HIF-1alpha siRNA. In contrast, in renal carcinoma cells that constitutively express HIF-1alpha and HIF-2alpha due to loss of VHL function, we found that high basal VEGF, glucose transporter-1, urokinase-type plasminogen activator receptor, and plasminogen activator inhibitor-1 expression was predominantly dependent on HIF-2alpha. Finally, we showed that a newly identified small-molecule inhibitor of HIF-1, NSC-134754, is also able to significantly decrease HIF-2alpha protein expression and HIF-2alpha-regulated VEGF levels in renal carcinoma cells. Our data have important implications for how we target the HIF pathway therapeutically.
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PMID:Role of hypoxia-inducible factor (HIF)-1alpha versus HIF-2alpha in the regulation of HIF target genes in response to hypoxia, insulin-like growth factor-I, or loss of von Hippel-Lindau function: implications for targeting the HIF pathway. 1677 2

Recent studies have demonstrated a role for telomerase in driving tumor progression, but its mechanism of action remains unclear. Here we show that stable, ribozyme-mediated suppression of mouse telomerase RNA reduced telomerase RNA expression, telomerase activity, and telomere length, which significantly reduced tumor invasion and metastatic potential. Our studies reveal that previously unidentified effects of telomerase may mediate its tumor-promoting effects. First, reducing telomerase activity induced a more dendritic morphology, accompanied by increased melanin content and increased expression of tyrosinase, a key enzyme in melanin biosynthesis. Second, gene expression profiling revealed that telomerase targeting down-regulated expression of several glycolytic pathway genes, with a corresponding decrease in glucose consumption and lactate production. Thus, telomerase activity controls the glycolytic pathway, potentially altering the energy state of tumor cells and thereby modulating tyrosinase activity and melanin production. These studies have important implications for understanding the mechanisms by which telomerase promotes tumor invasion and metastasis.
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PMID:Genes and pathways downstream of telomerase in melanoma metastasis. 1684 66

It has been established that as molecular chaperones, the glucose-regulated proteins (GRPs) play an important role in maintaining cellular homeostasis. This conventional concept of GRPs as protein folding chaperones is updated by discoveries that GRPs promote tumor proliferation, metastasis, drug resistance, immunotherapy, which have major clinical implications in the prognosis and treatment of cancer. Further, the localization of GRPs on the cell surface of certain cell types suggests that they serve new functions as cell surface receptors for signaling. These and other new developments on the role of GRP78, GRP94 and GRP170 in cancer progression and therapy are discussed in this review.
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PMID:Glucose regulated proteins in cancer progression, drug resistance and immunotherapy. 1686 2

Insulin resistance is a worldwide risk factor for the two most dangerous human disease groups; namely, for cardiovascular lesions and malignancies. The insulin resistance syndrome have five basic criteria: hyperglycemia, visceral obesity, elevated serum triglyceride level, low HDL-cholesterol level (dyslipidemia) and hypertension. Each of these criteria alone are risk factors for cancer, and they mean together a multiple risk. Insulin resistance of the liver, skeletal muscles, and fatty tissue leads to a reactive hyperinsulinemia by the increased secretory activity of the beta-cells. Insulin has diverse metabolic effects, and at the same time is a growth factor. It enhances the production and mitogenic activity of other, insulin-like growth factors, and leads to pathological cell proliferation. In the uncompensated phase of insulin resistance hyperglycemia appears, which promotes tumor genesis by several pathways. The elevated serum glucose level is advantageous for the increased DNA synthesis of the tumor cells. It provokes deliberation of free radicals, which will cause derangement of both the DNA and the enzymes having a role in the repair mechanisms. Hyperglycemia leads to a nonenzymatic glycation of protein structures, and the glycated products enhance the deliberation of free radicals, cytokines and growth factors. Insulin resistance means an enhanced risk for breast, pancreas, liver, colon, bladder, prostate and oral cavity cancers. The moderately increased fasting glucose level is also a risk factor for breast, stomach and colon cancers, even without manifestation of type 2 diabetes. Insulin resistance promotes tumor progression as well. In cancer patients with hyperglycemia or type 2 diabetes, the rate of tumor recurrence, metastatic spread and fatal outcome is higher as compared with the tumor patients without metabolic disease. The correlation between insulin resistance and tumor promotion reveals new possibilities in the prevention and treatment of cancer. The healthy diet, physical activity and weight loss increase insulin sensitivity, and decrease the risk for both cardiovascular diseases and malignancies.
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PMID:[Correlations of insulin resistance and neoplasms]. 1688 76

von Hippel Lindau (VHL) disease is a hereditary cancer syndrome caused by biallelic inactivation of the VHL tumor suppressor gene. The most widely known function of VHL is to limit normoxic protein expression of hypoxia-inducible factor-alpha (HIF-alpha). Loss of the functional VHL gene causes constitutive stabilization of HIF-alpha that primarily up-regulates hypoxia-inducible genes even at normal oxygen concentration, which in turn contribute to VHL tumor progression. We report on the novel function of VHL in hepatic glucose storage and disposal. VHL deletion in adult mouse liver quickly leads to increased accumulation of glycogen granules as well as lipid droplets. This abnormal glycogen storage in VHL-inactivated liver arises at least in part from significantly reduced expression of two key liver-specific glucose metabolism genes, glucose transporter-2 (GLUT2) and glucose-6-phosphatase (G-6-Pase). The expression pattern of these genes in VHL knock-out liver was in contrast to that of well-known HIF target genes, such as PGK, Glut-1, VEGF, and EPO, all of which are highly elevated upon VHL inactivation. Our findings suggest that two distinct signaling pathways exist at the downstream of VHL controlling different sets of gene expression. Following VHL inactivation, one pathway causes oxygen-independent overexpression of classic hypoxia-inducible genes and the other one described here suppresses expression of the genes important for liver glucose metabolism.
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PMID:von Hippel Lindau tumor suppressor regulates hepatic glucose metabolism by controlling expression of glucose transporter 2 and glucose 6-phosphatase. 1720 15

Tumor ischemia participates in angiogenesis and cancer progression through cellular responses to hypoxia and nutrient deprivation. However, the contribution of amino acids limitation to this process remains poorly understood. Using serum-free cell culture conditions, we tested the impact of L-glutamine deprivation on metabolic and angiogenic responses in A549/8 carcinoma cells. In these cells, lowering glutamine concentration modified the cell cycle distribution and significantly induced apoptosis/necrosis. Although glutamine deprivation led to a HIF-independent increase in VEGF-A mRNA, the corresponding protein level remained low and correlated with the inhibition of protein synthesis and activation of the GCN2/eIF2alpha pathway. Limitation of glutamine availability also hampers hypoxia- and hypoglycemia-induced VEGF-A protein upregulation. Thus, glutamine deprivation may have no direct effect on VEGF-dependent angiogenesis, compared to hypoxia or to glucose deprivation, and may instead be detrimental to cancer progression by antagonizing ischemia-induced stresses.
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PMID:Acute L-glutamine deprivation compromises VEGF-a upregulation in A549/8 human carcinoma cells. 1734 20


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