Cancer as a defective network for NF-κB

In a recent review we addressed the role of the transcription factor NF-κB, in shaping the cancer microenvironment. NF-κB, which interacts with chromatin modulators by cell-specific dynamics, controls cell interactions during inflammation, and its abnormal feedback regulation is implicated in cancer. Inflammation normally reprograms cells through changes in key topological elements of chromosomal DNA. As a result, inflammation overrides cell phenotype: initially, reprogramming cell function halts processes that impede the response of a damaged tissue to the cause of the harm, and eventually, late reprogramming of cells will replenish tissue structure and restore function. Each cell type provides a distinct resource for restoration of tissue integrity, tissue function, and for replenishment of the responsiveness of the immune system. Modulators of NF-κB transcriptional activity alter key aspects of gene expression and tissue integrity. NF-κB network alterations confer transcriptional plasticity to cancer

Unc119, a Novel Activator of Lck/Fyn, Is Essential for T Cell Activation

The first step in T cell receptor for antigen (TCR) signaling is the activation of the receptor-bound Src kinases, Lck and Fyn. The exact mechanism of this process is unknown. Here, we report that the novel Src homology (SH) 3/SH2 ligand–Uncoordinated 119 (Unc119) associates with CD3 and CD4, and activates Lck and Fyn. Unc119 overexpression increases Lck/Fyn activity in T cells. In Unc119-deficient T cells, Lck/Fyn activity is dramatically reduced with concomitant decrease in interleukin 2 production and cellular proliferation. Reconstitution of cells with Unc119 reverses the signaling and functional outcome. Thus, Unc119 is a receptor-associated activator of Src-type kinases. It provides a novel mechanism of signal generation in the TCR complex

Dynamic aberrant NF-κB spurs tumorigenesis: A new model encompassing the microenvironment

Recently it was discovered that a transient activation of transcription factor NF-κB can give cells properties essential for invasiveness and cancer initiating potential. In contrast, most oncogenes to date were characterized on the basis of mutations or by their constitutive overexpression. Study of NF-κB actually leads to a far more dynamic perspective on cancer: tumors caused by diverse oncogenes apparently evolve into cancer after loss of feedback regulation for NF-κB. This event alters the cellular phenotype and the expression of hormonal mediators, modifying signals between diverse cell types in a tissue. The result is a disruption of stem cell hierarchy in the tissue, and pervasive changes in the microenvironment and immune response to the malignant cells

Analysis Of Stk11/Lkb1 Gene Using Bioinformatics Tools

Aim: The STK11 gene, also known as LKB1, encodes for a serine/threonine kinase with growth-suppressing activity, such as inhibition of cell cycle progression, cell growth retardation, apoptotic cell death, and cell polarity control. This study aimed to investigate some properties of the STK11 gene and its product, such as the homologous protein sequences in different species, the common transcription factor binding sites on their promoters, their phylogenetic relationship, their catalytic domains (S_TKc), and their expression profiles. Methods: We investigated the homology, conserved domain, promoter and expression profiles of the STK11/LKB1 genes in various species using bioinformatics approaches. Results: Our results revealed that STK11/LKB1 molecules are conserved among all organisms investigated. The kinase domain (S_TKc) of human STK11/LKB1 gene is closest to those of Pan troglodytes, Macaca mulatta and Macaca fascicularis. In contrast, the most diverse to the human S_TKc domain is that of Bos taurus. With the multiple alignment strategy, protein and domain sequences of M. fascicularis and B. Taurus are predicted to have a truncation. The comparative screening of the promoters demonstrated that STK11/LKB1 genes do not seem to have any common conserved transcription factor binding sites. Conclusion: This study demonstrated STK11 molecules in various species are well conserved throughout evolution. Comparative screening of the promoter sequences of the human STK11 and its homologues found in the NCBI database revealed that there was no any common transcription factor binding sites. Phylogenetic trees constructed using the neighbor-joining method (NJ) revealed a close evolutionary relationship of S_TKc in various species

Concanavalin A and Phytohaemagglutinin Stimulated Lymphoproliferative Responses in Cord Blood Mononuclear Cells

Experimental and clinical evidences have demonstrated that umbilical cord blood is an efficient source of transplantable haematopoietic stem and progenitor cells. After transplantation, initial exposure to alloantigen-presenting cells (allo-APC) induced lymphoproliferative responses in cord blood T cells. However, this response is lower than that by adult T cells. The aim of this study was to investigate and compare lymphoprolifertive responses of cord blood mononuclear cells (CBMC) and adult peripheral blood mononuclear cells (PBMC). CBMC and PBMC immunoproliferative responses were measured by MTT assay after stimulation of respective primary culture cells with phytohaemagglutinin (PHA) or Concanavalin A (Con A) for 76 hours. Lymphoproliferative response of CBMC was significantly lower compared to that of PBMC

Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma

Epstein-Barr virus (EBV) is associated with several B and epithelial cell cancers. EBV-encoded latent membrane protein 2A (LMP2A) contributes to cellular transformation by mimicking B cell receptor signaling. LMP2A/MYC double transgenic mice develop splenomegaly and B cell lymphoma much faster than MYC transgenic mice do. In this study, we explored the potential therapeutic efficacy of a novel spleen tyrosine kinase (SYK) and FLT3 inhibitor TAK-659 for development of a treatment option for EBV-associated malignancies. In our transgenic model, TAK-659 treatment totally abrogated splenomegaly and tumor development in LMP2A/MYC mice in both pretumor and tumor cell transfer experiments. TAK-659 treatment killed tumor cells, but not host cells within the spleen and tumors. Furthermore, TAK-659 treatment abrogated metastasis of tumor cells into bone marrow. Our data also show that TAK-659 inhibits SYK phosphorylation and induces apoptosis in LMP2A/MYC tumor cells at low nanomolar concentrations. Therefore, TAK-659 may provide an effective therapeutic option for treatment of LMP2A-positive EBV-associated malignancies and should be explored further in clinical trials