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

The contribution of bacterial infection to tumorigenesis is usually ascribed to infection-associated inflammation. An alternate view is that direct interaction of bacteria with tumor cells promotes tumor progression. Here, we show that the microenvironment of large tumors favors bacterial survival, which in turn directly accelerates tumor growth by activating tumor cell Toll-like receptors (TLR). Listeria monocytogenes (Lm) survives in the microenvironment of large but not small tumors, resulting in the promotion of tumor growth. Lm did not affect the percentage of regulatory T cells or myeloid suppressor cells in the tumor. Through TLR2 signaling, Lm activated mitogen-activated protein kinases and nuclear factor-kappaB in tumor cells, resulting in the increased production of nitric oxide and interleukin-6 and increased proliferation of tumor cells. All of these effects were abrogated by silencing expression of TLR2, but not TLR4. The interaction of Helicobacter pylori with tumor cells from gastric carcinoma patients resulted in similar effects. These findings provide a new insight into infection-associated tumorigenesis and illustrate the importance of antibiotic therapy to treat tumors with bacterial infiltration.
 ...
PMID:Listeria monocytogenes promotes tumor growth via tumor cell toll-like receptor 2 signaling. 3141 50

Age-regulated genes may serve as markers of aging, enabling assessment of physiological aging independent of chronological age. One gene with transcripts that increase in abundance with age in human organs, inter alia in epithelial skin cells, is the chemokine growth-regulated protein alpha (GRO-alpha). When chemokines, such as GRO-alpha, become disregulated so that they are chronically expressed, tissue damage, angiogenesis, and tumorigenesis can follow. To consider the role of GRO-alpha as a potential marker for aging and cancer, we compared the transient knockdown of GRO-alpha by RNA interference in the human sebaceous gland cell line SZ95, which behaves like normal human sebocytes, and in the melanoma cell line A375, which originates from a primary human tumor. The reduced GRO-alpha RNA expression, of about 75% in SZ95 sebocytes and 58% in A375 melanoma cells, has functional consequences in normal aged cells and in cancer cells. Silencing of the proangiogenic chemokine GRO-alpha is proportionally correlated with interleukin-6 (IL-6), IL-8 and vascular endothelial growth factor secretion in both cell types. Thus, GRO-alpha may be a novel diagnostic marker for age-related pathology, including cancer.
 ...
PMID:GRO-alpha: a potential marker for cancer and aging silenced by RNA interference. 1805 65

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.
 ...
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

Gene alterations in tumor cells that confer the ability to grow under nutrient- and mitogen-deficient conditions constitute a competitive advantage that leads to more-aggressive forms of cancer. The atypical protein kinase C (PKC) isoform, PKCzeta, has been shown to interact with the signaling adapter p62, which is important for Ras-induced lung carcinogenesis. Here we show that PKCzeta-deficient mice display increased Ras-induced lung carcinogenesis, suggesting a new role for this kinase as a tumor suppressor in vivo. We also show that Ras-transformed PKCzeta-deficient lungs and embryo fibroblasts produced more interleukin-6 (IL-6), which we demonstrate here plays an essential role in the ability of Ras-transformed cells to grow under nutrient-deprived conditions in vitro and in a mouse xenograft system in vivo. We also show that PKCzeta represses histone acetylation at the C/EBPbeta element in the IL-6 promoter. Therefore, PKCzeta, by controlling the production of IL-6, is a critical signaling molecule in tumorigenesis.
 ...
PMID:Protein kinase Czeta represses the interleukin-6 promoter and impairs tumorigenesis in vivo. 1895 1

Increased dietary fat consumption is associated with colon cancer development. The exact mechanism by which fat induces colon cancer is not clear, however, increased bile acid excretion in response to high-fat diet may promote colon carcinogenesis. The farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, and bile acids are endogenous ligands of FXR. FXR is highly expressed in the intestine and liver where FXR is essential for maintaining bile acid homeostasis. The role of FXR in intestine cancer development is not known. The current study evaluated the effects of FXR deficiency in mice on intestinal cell proliferation and cancer development. The results showed that FXR deficiency resulted in increased colon cell proliferation, which was accompanied by an up-regulation in the expression of genes involved in cell cycle progression and inflammation, including cyclin D1 and interleukin-6. Most importantly, FXR deficiency led to an increase in the size of small intestine adenocarcinomas in adenomatous polyposis coli mutant mice. Furthermore, after treatment with a colon carcinogen, azoxymethane, FXR deficiency increased the adenocarcinoma multiplicity and size in colon and rectum of C57BL/6 mice. Loss of FXR function also increased the intestinal lymphoid nodule numbers in the intestine. Taken together, the current study is the first to show that FXR deficiency promotes cell proliferation, inflammation, and tumorigenesis in the intestine, suggesting that activation of FXR by nonbile acid ligands may protect against intestinal carcinogenesis.
 ...
PMID:Farnesoid X receptor deficiency in mice leads to increased intestinal epithelial cell proliferation and tumor development. 1898 Dec 89

The ras oncogene needs a second factor to induce transformation and tumorigenicity of the cell. In this study, we show that mouse fibroblast 7-4-Stat3C cells overexpressing both Ha-ras(val12) oncogene and active-form Stat3 (Stat3C) showed higher colony formation in soft agar and xenograft tumor growth in BALB/c mice. Further studies show that both serine-727 and tyrosine-705 of Stat3 were phosphorylated while Ha-ras was overexpressed. Interleukin-6 (IL-6)-induced phosphorylation of tyrosine-705 and serine-727, as well as DNA-binding and transcriptional activity of Stat3 were further enhanced by Ha-ras overexpression. In addition, overexpression of Stat3C in 7-4-Stat3C cells prevented the cells from morphological change and apoptosis triggered by the Ha-ras oncogene under serum-depleted conditions. We demonstrate that Ha-ras and Stat3 acting together synergistically induce Stat3 phosphorylation at serine-727 phosphorylation and cyclin D1 expression and further enhance transformation and tumorigenicity of the cell. Ha-ras-induced Stat3 phosphorylation at serine-727 plays a pivotal role in transcriptional activation of cyclin D1 and suppression of cell apoptosis. The effect of Ha-ras on Stat3 phosphorylation at serine-727 was also detected in human bladder (T24) and lung (H460) cancer cells. Stat3 phosphorylation at serine-727 is important in Ras-related tumorigenesis.
 ...
PMID:Ha-ras oncogene-induced Stat3 phosphorylation enhances oncogenicity of the cell. 1918 94

The double-stranded RNA-dependent protein kinase (PKR) plays a critical role in various biological responses including antiviral defense, cell differentiation, apoptosis, and tumorigenesis. In this study, we investigated whether PKR could affect the post-translational modifications of STAT1 protein and whether these modifications regulate osteoblast differentiation. We demonstrated that PKR was necessary for the ubiquitination of STAT1 protein. The expressions of bone-related genes such as type I collagen, integrin binding sialoprotein, osteopontin, and osterix were suppressed in osteoblasts lacking PKR activity. In contrast, the expressions of interleukin-6 and matrix metalloproteinases 8 and 13 increased in PKR-mutated osteoblasts. The expression and degradation of STAT1 protein were regulated by PKR in a SLIM-dependent pathway. Inhibition of SLIM by RNA interference resulted in the decreased activity of Runx2 in osteoblasts. Stimulation of interleukin-6 expression and suppression of alkaline phosphatase activity were regulated through by SLIM-dependent pathway. However, expressions of bone-related genes and MMPs were regulated by SLIM-independent pathway. Our present results suggest that the aberrant accumulation of STAT1 protein induced by loss of PKR regulate osteoblast differentiation through both SLIM/STAT1-dependent and -independent pathways.
 ...
PMID:PKR-mediated degradation of STAT1 regulates osteoblast differentiation. 1923 Aug 33

The binding of interleukin-6 (IL-6) cytokine family ligands to the gp130 receptor complex activates the Janus kinase (JAK)/ signal transducer and activator of transcription 3 (STAT3) signal transduction pathway, where STAT3 plays an important role in cell survival and tumorigenesis. Constitutive activation of STAT3 has been frequently observed in many cancer tissues, and thus, blocking of the gp130 signaling pathway, at the JAK level, might be a useful therapeutic approach for the suppression of STAT3 activity, as anticancer therapy. AG490 is a tyrphostin tyrosine kinase inhibitor that has been extensively used for inhibiting JAK2 in vitro and in vivo. In this study, we demonstrate a novel mechanism associated with AG490 that inhibits the JAK/STAT3 pathway. AG490 induced downregulation of gp130, a common receptor for the IL-6 cytokine family compounds, but not JAK2 or STAT3, within three hours of exposure. The downregulation of gp130 was not caused by enhanced degradation of gp130 or by inhibition of mRNA transcription. It most likely occurred by translation inhibition of gp130 in association with phosphorylation of the eukaryotic initiation factor-2alpha . The inhibition of protein synthesis of gp130 by AG490 led to immediate loss of mature gp130 in cell membranes, due to its short half-life, thereby resulting in reduction in the STAT3 response to IL-6. Taken together, these results suggest that AG490 blocks the STAT3 activation pathway via a novel pathway.
 ...
PMID:Janus Kinase 2 Inhibitor AG490 Inhibits the STAT3 Signaling Pathway by Suppressing Protein Translation of gp130. 1988 8

Interleukin-6 (IL-6) has been implicated in tumorigenesis; however, its role is still far from being clearly defined. Regulation of IL-6 expression is highly complex, and additional complexity is introduced by single-nucleotide polymorphisms in the IL-6 gene. These single-nucleotide polymorphisms might influence mRNA transcription, which might in turn result in increased susceptibility to certain tumors. The aim of this study was to analyze IL-6 mRNA and protein expressions in sporadic colon cancer. Influence of IL-6-174 G/C polymorphism on IL-6 mRNA expression and sporadic colon cancer susceptibility was evaluated as well. The frequency of IL-6-174 G/C was analyzed by polymerase chain reaction-restriction fragment length polymorphism analysis. IL-6 mRNA and protein expressions were analyzed by real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. No statistically significant difference in IL-6 mRNA expression in tumor tissue compared with the corresponding normal tissue was observed (p = 0.116). No correlation was found between IL-6 mRNA and protein expressions and clinicopathological features of sporadic colon tumors. There was no association of IL-6-174 G/C genotypes with IL-6 mRNA expression in colon tumors and corresponding normal mucous tissue (p = 0.355; p = 0.152). Finally, there was no association of IL-6-174 G/C with susceptibility to sporadic colon cancer.
 ...
PMID:Interleukin-6-174 G/C polymorphism is not associated with IL-6 expression and susceptibility to sporadic colon cancer. 2013 36

Mesenchymal stem cells (MSCs) are a heterogeneous population of non-hematopoietic precursor cells predominantly found in the bone marrow. They have been recently reported to home towards the hypoxic tumor microenvironment in vivo. Interleukin-6 is a multifunctional cytokine normally involved in the regulation of the immune and inflammatory response. In addition to its normal function, IL-6 signaling has been implicated in tumorigenesis. Solid tumors develop hypoxia as a result of inadequate O(2) supply. Interestingly, tumor types with increased levels of hypoxia are known to have increased resistance to chemotherapy as well as increased metastatic potential. Here, we present evidence that under hypoxic conditions (1.5% O(2)) breast cancer cells secrete high levels of IL-6, which serve to activate and attract MSCs. We now report that secreted IL-6 acts in a paracrine fashion on MSCs stimulating the activation of both Stat3 and MAPK signaling pathways to enhance migratory potential and cell survival. Inhibition of IL-6 signaling utilizing neutralizing antibodies leads to attenuation of MSC migration. Specifically, increased migration is dependent on IL-6 signaling through the IL-6 receptor. Collectively, our data demonstrate that hypoxic tumor cells specifically recruit MSCs, which through activation of signaling and survival pathways facilitate tumor progression.
 ...
PMID:Interleukin 6 mediated recruitment of mesenchymal stem cells to the hypoxic tumor milieu. 2063 53


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>