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      Combinatorial treatment with polyI:C and anti-IL6 enhances apoptosis and suppresses metastasis of lung cancer cells.

      Oncotarget

      Impact Journals LLC

      polyI:C-TLR3 suppression of survival and metastasis, JAK2/STAT3 antagonists, anti-IL6 antibody, cytokines and caspase 3/7 apoptosis, lung cancer cells

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          Abstract

          Activation of TLR3 stimulates cancer cell apoptosis and triggers secretion of inflammatory cytokines. PolyI:C, a TLR3 agonist, activates immune cells and regresses metastatic lung cancer in vivo. Although polyI:C reportedly kills lung carcinomas, the mechanism remains elusive. Here, we demonstrated that polyI:C suppressed the proliferation and survival of metastatic (NCI-H358 and NCI-H292) and non-metastatic (A549) lung cancer cells. Notably, A549, NCI-H292 and NCI-H358 which are inducible by polyI:C, expressed low-to-medium level of TLR3 protein, and were susceptible to polyI:C treatment. By contrast, NCI-H1299, which endogenously expresses high level of TLR3 protein, was insensitive to polyI:C. We showed that polyI:C stimulated pro-inflammatory cytokines associated with survival and metastasis in a cell type-specific manner. While A549 and NCI-H292 released high levels of IL6, IL8 and GRO, the NCI-H358 cells endogenously secretes abundant levels of these cytokines, and was not further induced by polyI:C. Thus, NCI-H358 was resistant to the inhibition of cytokine-dependent metastasis. NCI-H1299, which was unresponsive to polyI:C, did not produce any of the pro-inflammatory cytokines. Treatment of A549 with a combination of polyI:C and anti-IL6 antibody significantly decreased IL6 production, and enhanced polyI:C-mediated killing and suppression of oncogenicity and metastasis. While polyI:C stimulated the phosphorylation of STAT3 and JAK2, blockade of these proteins enhanced polyI:C-mediated suppression of survival and metastasis. Taken together, polyI:C alone provoked apoptosis of lung cancer cells that express low-to-medium levels of functional TLR3 protein. The combinatorial treatment with polyI:C and anti-IL6 enhanced polyI:C-mediated anticancer activities through IL6/JAK2/STAT3 signalling, and apoptosis via TLR3-mediated caspase 3/8 pathway.

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          Most cited references 55

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          Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method.

           K Livak,  T Schmittgen (2001)
          The two most commonly used methods to analyze data from real-time, quantitative PCR experiments are absolute quantification and relative quantification. Absolute quantification determines the input copy number, usually by relating the PCR signal to a standard curve. Relative quantification relates the PCR signal of the target transcript in a treatment group to that of another sample such as an untreated control. The 2(-Delta Delta C(T)) method is a convenient way to analyze the relative changes in gene expression from real-time quantitative PCR experiments. The purpose of this report is to present the derivation, assumptions, and applications of the 2(-Delta Delta C(T)) method. In addition, we present the derivation and applications of two variations of the 2(-Delta Delta C(T)) method that may be useful in the analysis of real-time, quantitative PCR data. Copyright 2001 Elsevier Science (USA).
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            Hallmarks of Cancer: The Next Generation

            The hallmarks of cancer comprise six biological capabilities acquired during the multistep development of human tumors. The hallmarks constitute an organizing principle for rationalizing the complexities of neoplastic disease. They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metastasis. Underlying these hallmarks are genome instability, which generates the genetic diversity that expedites their acquisition, and inflammation, which fosters multiple hallmark functions. Conceptual progress in the last decade has added two emerging hallmarks of potential generality to this list-reprogramming of energy metabolism and evading immune destruction. In addition to cancer cells, tumors exhibit another dimension of complexity: they contain a repertoire of recruited, ostensibly normal cells that contribute to the acquisition of hallmark traits by creating the "tumor microenvironment." Recognition of the widespread applicability of these concepts will increasingly affect the development of new means to treat human cancer. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Microorganisms that invade a vertebrate host are initially recognized by the innate immune system through germline-encoded pattern-recognition receptors (PRRs). Several classes of PRRs, including Toll-like receptors and cytoplasmic receptors, recognize distinct microbial components and directly activate immune cells. Exposure of immune cells to the ligands of these receptors activates intracellular signaling cascades that rapidly induce the expression of a variety of overlapping and unique genes involved in the inflammatory and immune responses. New insights into innate immunity are changing the way we think about pathogenesis and the treatment of infectious diseases, allergy, and autoimmunity.
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                Author and article information

                Journal
                28427199
                10.18632/oncotarget.15862

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