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 inflammation-associated cytokine interleukin-6 (IL-6) can contribute to tumor growth and resistance to therapy by the activation of survival mechanisms. In several human cancers, IL-6-activated survival signaling involves the signal transducers and activators of transcription (Stat) factors or protein kinase cascades. microRNAs (miRNAs) are endogenous regulators of gene expression that are altered in expression in many cancers. However, the effect of inflammatory cytokines on miRNA expression and the role of miRNA in modulating IL-6-mediated cell survival are unknown. We investigated the involvement of miRNA in malignant cholangiocytes stably transfected to overexpress IL-6, which enhances tumor growth in vivo by inhibition of apoptosis. We provide evidence that (i) miRNA expression both in vitro and in vivo is altered by overexpression of IL-6; (ii) selective miRNAs including let-7a are up-regulated and contribute to the survival effects of enforced IL-6 activity; and (iii) let-7a contributes to the constitutively increased phosphorylation of Stat-3 by a mechanism involving the neurofibromatosis 2 (NF2) gene. These findings reveal a novel mechanism by which IL-6 mediates tumor cell survival that may be therapeutically targeted and emphasize the presence of complex interrelationships between deregulated expression of miRNA and transcription factors in human cancers.
 ...
PMID:The MicroRNA let-7a modulates interleukin-6-dependent STAT-3 survival signaling in malignant human cholangiocytes. 1722 Mar 1

Mistletoe extracts are widely used in complementary and alternative cancer therapy in Europe. The extracts possess cytotoxic, as well as immunostimulatory effects. However, some investigators have suggested that low doses of mistletoe extracts could also induce tumor growth. The mistletoe extracts Helixor A, Helixor M and Helixor P were investigated for growth inhibitory and stimulatory effects in a panel of 38 human tumor cell lines in vitro. Mistletoe lectin I (ML-1), adriamycin and interleukin-6 (IL-6) were used as reference compounds. All three mistletoe preparations showed cytotoxic activity [T/C (Test/Control) < 30%]: Helixor P was the most potent, followed by Helixor M and Helixor A with IC50 (50% inhibitory concentration) values of 68.4, 114 and 133 microg/ml, respectively. The IC50 values of ML-1 and adriamycin were 0.026 and 0.069 microg/ml. None of the human tumor cell lines in the panel showed growth stimulation (T/C (Test/Control) > 125%) by the mistletoe extracts or ML-1, apart from two exceptions in the colon carcinoma cell line HCC-2998, in which Helixor M and ML-1 showed a marginal stimulation (TIC 128% and 131%, respectively) at one concentration only. Further investigations into the latter effect of Helixor M and ML-1 in the HCC-2998 line using five different proliferation assays, modified cell culture conditions and the identical production charge of mistletoe extract, as well as a new one, did not confirm the previous observation. It was concluded that the marginal stimulation found in the earlier experiments was a statistical coincidence. Helixor mistletoe preparations and ML-1 have cytotoxic activity and do not stimulate tumor cell proliferation in vitro which is in accordance with previous scientifically based observations on aqueous mistletoe extracts.
 ...
PMID:Cytotoxic activity and absence of tumor growth stimulation of standardized mistletoe extracts in human tumor models in vitro. 1735 37

Here we investigated the cytotoxicity of JS-K, a prodrug designed to release nitric oxide (NO(*)) following reaction with glutathione S-transferases, in multiple myeloma (MM). JS-K showed significant cytotoxicity in both conventional therapy-sensitive and -resistant MM cell lines, as well as patient-derived MM cells. JS-K induced apoptosis in MM cells, which was associated with PARP, caspase-8, and caspase-9 cleavage; increased Fas/CD95 expression; Mcl-1 cleavage; and Bcl-2 phosphorylation, as well as cytochrome c, apoptosis-inducing factor (AIF), and endonuclease G (EndoG) release. Moreover, JS-K overcame the survival advantages conferred by interleukin-6 (IL-6) and insulin-like growth factor 1 (IGF-1), or by adherence of MM cells to bone marrow stromal cells. Mechanistic studies revealed that JS-K-induced cytotoxicity was mediated via NO(*) in MM cells. Furthermore, JS-K induced DNA double-strand breaks (DSBs) and activated DNA damage responses, as evidenced by neutral comet assay, as well as H2AX, Chk2 and p53 phosphorylation. JS-K also activated c-Jun NH(2)-terminal kinase (JNK) in MM cells; conversely, inhibition of JNK markedly decreased JS-K-induced cytotoxicity. Importantly, bortezomib significantly enhanced JS-K-induced cytotoxicity. Finally, JS-K is well tolerated, inhibits tumor growth, and prolongs survival in a human MM xenograft mouse model. Taken together, these data provide the preclinical rationale for the clinical evaluation of JS-K to improve patient outcome in MM.
 ...
PMID:JS-K, a GST-activated nitric oxide generator, induces DNA double-strand breaks, activates DNA damage response pathways, and induces apoptosis in vitro and in vivo in human multiple myeloma cells. 1738 1

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

Activation of the extracellular signal-regulated kinase1/2 (ERK1/2) signaling cascade mediates human multiple myeloma (MM) growth and survival triggered by cytokines and adhesion to bone marrow stromal cells (BMSCs). Here, we examined the effect of AZD6244 (ARRY-142886), a novel and specific MEK1/2 inhibitor, on human MM cell growth in the bone marrow (BM) milieu. AZD6244 blocks constitutive and cytokine-stimulated ERK1/2 phosphorylation and inhibits proliferation and survival of human MM cell lines and patient MM cells, regardless of sensitivity to conventional chemotherapy. Importantly, AZD6244 (200 nM) induces apoptosis in patient MM cells, even in the presence of exogenous interleukin-6 or BMSCs associated with triggering of caspase 3 activity. AZD6244 sensitizes MM cells to both conventional (dexamethasone) and novel (perifosine, lenalidomide, and bortezomib) therapies. AZD6244 down-regulates the expression/secretion of osteoclast (OC)-activating factors from MM cells and inhibits in vitro differentiation of MM patient PBMCs to OCs induced by ligand for receptor activator of NF-kappaB (RANKL) and macrophage-colony stimulating factor (M-CSF). Finally, AZD6244 inhibits tumor growth and prolongs survival in vivo in a human plasmacytoma xenograft model. Taken together, these results show that AZD6244 targets both MM cells and OCs in the BM microenvironment, providing the preclinical framework for clinical trials to improve patient outcome in MM.
 ...
PMID:Targeting MEK induces myeloma-cell cytotoxicity and inhibits osteoclastogenesis. 1751 Mar 21

In view of our previous findings that tumor cell-derived macrophage migration inhibitory factor (MIF) increased macrophage-mediated ovarian cancer cell invasiveness in vitro, we investigated the wider significance of ovarian cancer cell-derived MIF for tumor growth, metastasis, and angiogenesis. We found that MIF is expressed in borderline and malignant ovarian tumors, and active MIF is found in malignant ascitic fluid. We next investigated the expression and function of MIF in a syngeneic ovarian cancer model. Stable knockdown of MIF in the murine ovarian cancer cell line ID8 decreased in vivo tumor burden and overall survival. Tumors arising from MIF knockdown cells had decreased proliferation and significantly increased apoptosis. This was associated with an increased phosphorylation of p53 and reduced Akt phosphorylation. MIF knockdown led to a changed cytokine profile in the ascitic microenvironment; tumor necrosis factor-alpha, interleukin-6 (IL-6), and IL-10 expression were all significantly decreased. Accompanying this decrease in cytokine expression was a significant decrease in macrophage infiltration into ascites. Additionally, MIF knockdown reduced the expression of proangiogenic cytokines vascular endothelial growth factor and keratinocyte chemoattractant (KC) and reduced the amount of endothelial cells in the malignant ascites. We conclude that autocrine production of MIF by ovarian cancer cells stimulates other cytokines, chemokines, and angiogenic factors that may promote colonization of the peritoneum and neovascularization of tumor deposits.
 ...
PMID:Ovarian cancer cell-derived migration inhibitory factor enhances tumor growth, progression, and angiogenesis. 1762 Apr 29

Interleukin-6 (IL-6) is overexpressed and contributes to tumor cell growth in cholangiocarcinoma. Enforced IL-6 production can alter the expression of specific microRNAs (miRNAs) involved in tumor growth, and moreover can modulate expression of methylation-dependent genes. Thus, we assessed the methylation-dependent regulation of miRNA expression in human malignant cholangiocytes stably transfected to overexpress IL-6. The expression of the methyltransferases DNA methyltransferase enzyme-1 and HASJ4442 was increased by IL-6 overexpression, but was decreased by the methylation inhibitor 5-aza-2'-deoxycytidine (5-aza-CdR). Expression profiling identified seven miRNAs that were significantly downregulated by IL-6 overexpression (<0.4-fold) and upregulated (>2-fold) by 5-aza-CdR. One of these, miR-370, is embedded in a CpG island. Although 5-aza-CdR increased miR-370 expression by 2.1-fold in malignant cells, the expression in nonmalignant cells was unchanged. The oncogene mitogen-activated protein kinase kinase kinase 8 (MAP3K8) was identified as a target of miR-370, and its expression was decreased by 5-aza-CdR in cholangiocarcinoma cells. Overexpression of IL-6 reduced miR-370 expression and reinstated MAP3K8 expression in vitro as well as in tumor cell xenografts in vivo. Thus, IL-6 may contribute to tumor growth by modulation of expression of selected miRNAs, such as miR-370. These studies define a mechanism by which inflammation-associated cytokines can epigenetically modulate gene expression and directly contribute to tumor biology.
 ...
PMID:Epigenetic regulation of microRNA-370 by interleukin-6 in malignant human cholangiocytes. 1762 Dec 67

Interleukin 6 and the signal transducer and activator of transcription (STAT) 3 proteins have important roles in cancer cell survival and proliferation. Recent studies demonstrate that abnormal STAT3 activation promotes tumor growth and supports survival of many human cancers, and thus, this protein or the pathway responsible for its activation is a potential target for the new anticancer therapy. STAT3 is a DNA binding transcription factor, and therefore, its function depends on nuclear translocation. To discover inhibitors of the STAT3 pathway, we designed a cell-based screening assay capable of identifying small molecules that inhibit nuclear translocation. Among the 2000-compound National Cancer Institute Diversity set, we identified 8-benzyl-4-oxo-8-azabicyclo[3.2.1]oct-2-ene-6,7-dicarboxylic acid (SD-1008) as a micromolar inhibitor of interleukin-6 or oncostatin-induced STAT3 nuclear translocation. In addition, SD-1008 inhibits tyrosyl phosphorylation of STAT3, Janus kinase 2 (JAK2), and Src. SD-1008 also reduces STAT3-dependent luciferase activity. Biochemical studies with recombinant JAK2 proteins demonstrate that high concentrations of SD-1008 directly inhibit JAK2 kinase autophosphorylation. Exposure of various cell lines to SD-1008 decreases levels of the STAT3-dependent proteins, Bcl-X(L) and survivin, inducing apoptosis. SD-1008 also enhances apoptosis induced by paclitaxel in ovarian cancer cells. These results demonstrate that SD-1008 directly blocks the JAK-STAT3 signaling pathway in human cancer cells that express constitutively active Stat and add to the growing literature that identifies this pathway as a viable target for drug development. Finally, SD-1008 may be a suitable prototype for further chemical modification and exploration as a therapeutic agent.
 ...
PMID:8-benzyl-4-oxo-8-azabicyclo[3.2.1]oct-2-ene-6,7-dicarboxylic acid (SD-1008), a novel janus kinase 2 inhibitor, increases chemotherapy sensitivity in human ovarian cancer cells. 1767 86

Interleukin-6 (IL6) is a growth and survival factor in human prostate cancer (PCa) cells with aggressive phenotypes and has been implicated in the progression of hormone refractory PCas. In the present study, we characterized the IL6-triggered PI3K/Akt and MAPK/Erk signaling. We identified the A-type cyclin, cyclin A1 as an important downstream target of PI3K/Akt. Treatment of cells with PI3K inhibitor or cotransfection with a vector expressing wild-type PTEN decreased cyclin A1 promoter activity. Cyclin A1 promoter activity and its expression were upregulated by constitutively active myristoylated Akt and were downregulated by dominant negative Akt in response to IL6 stimulation. LNCaP cells overexpressing cyclin A1 are resistant to camptothecin-induced apoptosis. Conversely, targeted knockdown of cyclin A1 via shRNA in LNCaP IL6+ cells resulted in decreased survival after treatment with camptothecin. This suggests that cyclin A1 is an important downstream target of PI3K/Akt that transduces survival signals in response to IL6 stimulation. Xenograft tumors generated from LNCaP-IL6+ cells expressing IL6 had higher levels of cyclin A1 and had rapid tumor growth compared to LNCaP xenograft tumors. Taken together, IL6 might utilize PI3K/Akt and cyclin A1 to promote tumor cell survival in PCa.
 ...
PMID:Interleukin-6 activates PI3K/Akt pathway and regulates cyclin A1 to promote prostate cancer cell survival. 1802 47

Although obesity has been consistently linked to an increased risk of several malignancies, including cancers of the colon, gallbladder, kidney, and pancreas, its role in prostate cancer etiology remains elusive. Data on the association between obesity and prostate cancer incidence are inconsistent, and in some studies obesity is associated with an increase in risk of high-grade prostate cancer but with a decrease in risk of low-grade tumors. In contrast, obesity has been consistently associated with an increased risk of prostate cancer aggressiveness and mortality. The differential effects of obesity on subtypes of prostate cancer suggest etiologic heterogeneity in these tumors and complex interactions between androgen metabolism and several putative risk factors, including insulin resistance, diabetes, inflammation, and genetic susceptibility, on prostate cancer risk. Data on the role of abdominal obesity, insulin resistance, and metabolic syndrome in prostate cancer etiology are limited. Obesity has been shown to be associated with a state of low-grade chronic inflammation, and insulin resistance and the metabolic syndrome are associated with adverse metabolic profiles and with higher circulating concentrations of inflammation-related markers, including leptin, interleukin-6, and tumor necrosis factor-, many of which have been shown to enhance tumor growth. Thus, whether obesity and metabolic syndrome modulate the risk of prostate cancer through chronic inflammation needs to be investigated further. Given that the prevalence of obesity and metabolic syndrome is increasing worldwide and that the world population is aging, the roles of obesity and metabolic syndrome in prostate carcinogenesis warrant further clarification.
 ...
PMID:Obesity, metabolic syndrome, and prostate cancer. 1826 78


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