Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P05231 (interleukin-6)
 23,907 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The suppressor of cytokine signalling-1 (SOCS-1) gene is frequently silenced in human hepatocellular carcinoma by aberrant methylation. The aim of this study was to determine if SOCS-1 is inactivated in pancreatic ductal neoplasms, and to investigate if aberrant methylation of this gene affected the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway. Aberrant methylation in the CpG island of the SOCS-1 gene was detected in six of 19 (31.6%) human pancreatic cancer cell lines using methylation-specific PCR, and was associated with a loss or reduction of gene expression in five of the six methylated cell lines. Thirteen of 60 pancreatic ductal adenocarcinomas (21.7%) and two of 34 intraductal papillary mucinous neoplasms (IPMNs) (5.9%) had methylated SOCS-1. In contrast, SOCS-1 methylation was not seen in pancreatic normal ductal epithelia (zero out of 15), in pancreatic intraepithelial neoplasia (PanINs) (zero out of 49) or in the IPMNs without infiltrating cancer (zero out of 20). 5-Aza-2'-deoxycytidine treatment of the SOCS-1-methylated pancreatic cancer cell lines led to restoration of SOCS-1 gene expression. Interleukin-6, which has been shown to act through the JAK/STAT pathway to increase cell growth, induced modest time and dose-dependent cell proliferation in a SOCS-1-methylated cell line (PL10, P=0.015) but not in two unmethylated cell lines. These results indicate that loss of SOCS-1 gene is associated with transcriptional silencing and may have growth-promoting effects, and that its methylation is a useful marker of pancreatic cancer.
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PMID:Aberrant methylation of suppressor of cytokine signalling-1 (SOCS-1) gene in pancreatic ductal neoplasms. 1286 27

At baseline, weight-losing pancreatic cancer patients (n=7) had lower leptin (P<0.05) but higher cortisol, interleukin-6, resting energy expenditure and fat oxidation than healthy subjects (n=6, P<0.05). Over a 4 h feeding period, the areas under the curve for glucose, cortisol and interleukin-6 were greater (P<0.05), but less for leptin in the cancer group (P<0.05). Therefore, it would appear that low leptin concentrations, increased fat oxidation and insulin resistance are associated with increased concentrations of cortisol and interleukin-6 in weight-losing patients with pancreatic cancer.
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PMID:The response of leptin, interleukin-6 and fat oxidation to feeding in weight-losing patients with pancreatic cancer. 1502 90

A disintegrin and metalloproteinase (ADAM) molecules are known for their unique potential to combine adhesion, proteolysis, and signaling. To understand the role of ADAM17/tumor necrosis factor-alpha (TNF-alpha) converting enzyme (TACE) in pancreatic ductal adenocarcinoma (PDAC), we investigated its expression, function, and in vitro regulation. ADAM17/TACE mRNA was expressed in 3 of 10 normal pancreatic tissues, 6 of 8 samples from patients with chronic pancreatitis, 10 of 10 PDAC tissues, and 9 of 9 pancreatic cancer cell lines, but it was absent in primary duct epithelial cells. Immunohistochemical staining revealed positive cancer cells in 8 of 10 PDACs but no staining of ducts in normal pancreas. ADAM17/TACE was found in 0 of 16 pancreatic intraepithelial neoplasia (PanIN)-1A lesions, 1 of 30 PanIN-1B lesions, 2 of 13 PanIN-2 lesions but, in 13 of 15 PanIN-3 lesions, associated with PDAC. Western blot, flow cytometry, and confocal microscopy analyses showed the aberrant expression of ADAM17/TACE protein in pancreatic cancer cell lines. The proteolytic activity of ADAM17/TACE, assessed by the release of TNF-alpha, was inhibited by TNF-alpha protease inhibitor. ADAM17/TACE gene silencing using small interfering RNA technique in vitro reduced invasion behavior dramatically, whereas proliferation was unaffected. Furthermore, ADAM17/TACE mRNA expression was down-regulated in pancreatic cancer cells arrested in G2-M phase as well as in a time-dependent manner after TNF-alpha and interleukin-6 incubation. In conclusion, our findings provide evidence of aberrant expression of the proteolytically active ADAM17/TACE in advanced precursor lesions (PanIN-3) and PDAC while identifying its critical involvement in the invasion process.
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PMID:Aberrant expression of a disintegrin and metalloproteinase 17/tumor necrosis factor-alpha converting enzyme increases the malignant potential in human pancreatic ductal adenocarcinoma. 1698 46

Severe or chronic disease can lead to cachexia which involves weight loss and muscle wasting. Cancer cachexia contributes significantly to disease morbidity and mortality. Multiple studies have shown that the metabolic changes that occur with cancer cachexia are unique compared to that of starvation. Specifically, cancer patients seem to lose a larger proportion of skeletal muscle mass. There are three pathways that contribute to muscle protein degradation: the lysosomal system, cytosolic proteases and the ubiquitin (Ub)-proteasome pathway. The Ub-proteasome pathway seems to account for the majority of skeletal muscle degradation in cancer cachexia and is stimulated by several cytokines including tumor necrosis factor-alpha, interleukin-1beta, interleukin-6, interferon-gamma and proteolysis-inducing factor. Cachexia is particularly severe in pancreatic cancer and contributes significantly to the quality of life and mortality of these patients. Several factors contribute to weight loss in these patients, including alimentary obstruction, pain, depression, side effects of therapy and a high catabolic state. Although no single agent has proven to halt cachexia in these patients there has been some progress in the areas of nutrition with supplementation and pharmacological agents such as megesterol acetate, steroids and experimental trials targeting cytokines that stimulate the Ub-proteasome pathway.
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PMID:Mechanisms of skeletal muscle degradation and its therapy in cancer cachexia. 1745 54

Although dendritic cell (DC) function is impaired in pancreatic cancer patients, the underlying mechanisms are unknown. This study analyzed the soluble factors released by pancreatic cancer cells responsible for inhibiting DC differentiation and activation. Medium conditioned by a highly metastatic human pancreatic cancer cell line BxPC-3 [BxPC-3 conditioned medium (BxCM)] was mainly used for the study. Both CD34+ hematopoietic progenitor cell-derived and CD14+ monocyte-derived immature DCs and mature DCs (mDCs) were inhibited by BxCM. Allostimulation of CD4+ and CD8+ T cells by BxCM-treated mDCs was inefficient and resulted in production of lower levels of Th1 and Th2 cytokines. Antigen-specific T-cell activation capability was also reduced in BxCM-treated mDCs. Addition of exogenous interleukin-6 (IL-6) and granulocyte colony-stimulating factor (G-CSF), which were present in high amounts in BxCM, mimicked the inhibitory effect of BxCM on DC differentiation and maturation. IL-6 was able to suppress DC differentiation and G-CSF mainly acted on the suppressing allostimulatory capacity of DCs. In addition, pancreatic cancer patient sera were able to inhibit DC differentiation of CD14+ monocytes obtained from healthy donors. Depleting IL-6 or G-CSF from BxCM could reverse the DC-inhibitory properties of BxCM. Furthermore, BxCM, IL-6, or G-CSF led to the activation of signal transducer and activator of transcription 3 (STAT3) in CD14+ monocytes to different degrees. Blocking BxCM-induced STAT3 activation also reversed the inhibitory effect of BxCM on DC differentiation. Therefore, IL-6 and G-CSF in BxCM represent two main factors responsible for suppression of DC differentiation, maturation, and antigen presentation, and this suppression of DC functions may be due to the aberrant activation of STAT3 by BxCM.
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PMID:Elevated interleukin-6 and G-CSF in human pancreatic cancer cell conditioned medium suppress dendritic cell differentiation and activation. 1754 30

Interleukin-6 (IL-6) is proinflammatory cytokine that produces multifunctional effects. It is also involved in the regulation of immune reactions, hematopoiesis and inflammatory state. Interleukin-6 has been shown to be associated with tumor progression including inhibition of cancer cells apoptosis and stimulation of angiogenesis. Anti-IL-6 therapy is a new strategy in the inflammatory autoimmune diseases and cancer. Clinical studies have shown elevated serum IL-6 concentrations in patients with endometrial cancer, non-small cell lung carcinoma, colorectal cancer, renal cell carcinoma, breast and ovarian cancer. Serum IL-6 levels correlate with tumor stage, and survival of patients. In this article we have focused on a role of IL-6 as a prognostic factor in several malignancies such as colorectal cancer, breast cancer, gastric cancer and pancreatic cancer.
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PMID:[Clinical significance of interleukin-6 (IL-6) as a prognostic factor of cancer disease]. 1803 Aug 75

The only universally accepted risk factors for the development of pancreatic cancer are a positive family history or a history of smoking. Although the contribution of pancreatitis to pancreatic carcinogenesis has been debated for decades in the epidemiology literature, the actual mechanism is still unclear. With the rising epidemic of obesity, scientists have begun to focus on the contribution of chronic inflammatory state of morbidly obese patients in an effort to better understand the contribution of inflammation to the comorbidities of obesity. Notably, population studies are beginning to show that one of the most serious potential comorbidities of obesity is an increased lifetime risk of developing cancer. In this article, the current literature that exists supporting this Chronic Inflammatory Hypothesis as it pertains to obesity and pancreatic carcinogenesis is reviewed. To date, studies have focused on interleukin-6, a cytokine known to play a role in obesity, chronic pancreatitis and pancreatic cancer. The anti-inflammatory adipocytokine, adiponectin, has also shown promise as a key player in this mechanism and has recently been found to be more specific than standard tumor markers in differentiating pancreatic cancer from chronic pancreatitis. If the pathogenesis of pancreatic cancer is related to hormone levels associated with obesity, such as adipocytokines, and cytokines associated with chronic inflammation, this could potentially lead to the development of new pancreatic cancer tumor markers and ultimately new therapies and methods of prevention.
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PMID:Obesity, pancreatitis, and pancreatic cancer. 1856 97

In current literature there is evidence that psychological factors can affect the incidence and progression of some cancers. Data obtained from animal models support the hypothesis that stress can be a cofactor. The underlying mechanisms for the association between psychological factors and pancreatic cancer are very poorly understood. In this study, we examined the possible growth promoting effects of the stress-associated hormone, norepinephrine, on immortalized human pancreatic duct epithelial cells. Our results suggest that norepinephrine can increase cell proliferation of human pancreatic duct epithelial cells. We also evaluated the ability of norepinephrine to induce interleukin-6 (IL-6), interleukin-10 (IL-10), and vascular endothelial growth factor (VEGF). All of which may promote oncogenesis of immortalized human pancreatic duct epithelial cells. We found that norepinephrine can increase the IL-6 and VEGF but not IL-10 levels secreted by human pancreatic duct epithelial cells. Since norepinephrine can increase cell proliferation of human pancreatic duct epithelial cells, we performed further testing to see if dietary agents, sulforaphane and resveratrol, can inhibit norepinephrine-mediated increases in cell proliferation in human pancreatic duct epithelial cells. Interestingly, our results demonstrated that sulforaphane but not resveratrol inhibits norepinephrine-mediated increases in cell viability in human pancreatic duct epithelial cells. Furthermore, sulforaphane also inhibits norepinephrine-mediated increase of the IL-6 levels but not VEGF levels. Our study is the first to demonstrate that stress-associated hormone, norepinephrine, can increase the cell proliferation and IL-6 levels of human pancreatic duct epithelial cells, which can be inhibited by sulforaphane, a chemopreventive agent and a natural compound from the Cruciferous vegetables.
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PMID:Stress-associated hormone, norepinephrine, increases proliferation and IL-6 levels of human pancreatic duct epithelial cells and can be inhibited by the dietary agent, sulforaphane. 1863 64

The acute phase protein response (APPR) and peripheral blood mononuclear cell-derived inflammatory cytokine production was assessed in patients with advanced pancreatic cancer and age-matched healthy volunteers. We examined the relationship between the APPR, cytokine production and survival in these patients. Forty-two patients with pancreatic cancer cachexia and twelve age-matched healthy controls were recruited. The nutritional status, Karnofsky performance score, C reactive protein (CRP), serum interleukin-6, and in vitro monocyte interleukin-1 and interleukin-6 production were measured. The dates of death of the pancreatic cancer patients were subsequently obtained and appropriate patient variables at baseline were entered into a Cox's proportional hazards model. The cancer patients had significantly lower: body mass index, Karnofsky performance score, serum albumin and elevated CRP and stimulated interleukin-6 production. Both univariate and multivariate analysis demonstrated a strong association between tumour stage, CRP, stimulated interleukin-6 production and survival. Monocytes in cachectic pancreatic cancer patients are primed to produce high levels of interleukin-6 when stimulated. Overproduction of interleukin-6 has a negative impact on survival. Decreased survival is associated with an elevated APPR. While the elevated APPR is probably related to locally produced interleukin-6 in the liver, it seems possible that locally and systemically produced interleukin-6 influences survival.
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PMID:Pro-inflammatory cytokine release by peripheral blood mononuclear cells from patients with advanced pancreatic cancer: relationship to acute phase response and survival. 1928 13

The Signal Transducer and Activator of Transcription (STAT) proteins comprise a family of latent transcription factors with diverse functions. STAT3 has well established roles in cell proliferation, growth and survival, and its persistent activation has been detected with high frequency in many human cancers. As constitutive activation of STAT3 appears to be vital for the continued survival of these cancerous cells, it has emerged as an attractive target for chemotherapeutics. We examined whether the inhibitory activities of bioactive compounds from cruciferous vegetables, such as Benzyl isothiocyanate (BITC) and sulforaphane, extended to STAT3 activation in PANC-1 human pancreatic cancer cells. BITC and sulforaphane were both capable of inhibiting cell viability and inducing apoptosis in PANC-1. Sulforaphane had minimal effect on the direct inhibition of STAT3 tyrosine phosphorylation, however, suggesting its inhibitory activities are most likely STAT3-independent. Conversely, BITC was shown to inhibit the tyrosine phosphorylation of STAT3, but not the phosphorylation of ERK1/2, MAPK and p70S6 kinase. These results suggest that STAT3 may be one of the targets of BITC-mediated inhibition of cell viability in PANC-1 cancer cells. In addition, we show that BITC can prevent the induction of STAT3 activation by Interleukin-6 in MDA-MB-453 breast cancer cells. Furthermore, combinations of BITC and sulforaphane inhibited cell viability and STAT3 phosphorylation more dramatically than either agent alone. These findings suggest that the combination of the dietary agents BITC and sulforaphane has potent inhibitory activity in pancreatic cancer cells and that they may have translational potential as chemopreventative or therapeutic agents.
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PMID:Dietary agent, benzyl isothiocyanate inhibits signal transducer and activator of transcription 3 phosphorylation and collaborates with sulforaphane in the growth suppression of PANC-1 cancer cells. 1971 81


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