Fas (CD95/APO-1) is a cell surface "death receptor" that mediates apoptosis upon engagement by its ligand, FasL. Paradoxically, Fas/FasL can also promote cell invasion among non-apoptotic cells; ...here, we show that Fas/FasL signaling can promote tumor invasion when apoptosis is compromised. We have developed a recombinant FasL Interfering Protein (FIP) to interfere with Fas signaling in C6 glioma cells expressing both Fas receptor and its ligand. FIP administration did not affect cell viability but impaired cell motility and invasiveness of glioma cells. Blockade of Fas signaling reduced MMP-2 activity in glioma cells, that was associated with down-regulation of MAPK signaling, and AP-1 and NFkappaB-driven transcription. FIP treatment did not affect mmp-2 and mt1-mmp expression but significantly attenuated timp-2 expression and TIMP-2 amount in the culture medium. Studies with pharmacological inhibitors of JNK/c-Jun (SP600125) and NFkappaB (BAY11-7082) signaling pathways demonstrated that timp-2 expression is regulated by NFkappaB transcription factor. Our findings show that non-apoptotic Fas signaling activated in the autocrine manner or through microenvironment derived factors can regulate invasiveness of glioma cells via modulation of MMP-2 activation, likely by controlling TIMP-2 expression.
Despite a conceptually simple mechanism of signaling, the JAK-STAT pathway exhibits considerable behavioral complexity. Computational pathway models are tools to investigate in detail signaling ...process. They integrate well with experimental studies, helping to explain molecular dynamics and to state new hypotheses, most often about the structure of interactions.
A relatively small amount of experimental data is available for a JAK1/2-STAT1 variant of the pathway, hence, only several computational models were developed. Here we review a dominant approach of kinetic modeling of the JAK1/2-STAT1 pathway, based on ordinary differential equations. We also give a brief overview of attempts to computationally infer topology of this pathway.
Fas (CD95/APO-1) is a cell surface "death receptor" that mediates apoptosis upon engagement by its ligand, FasL. Paradoxically, Fas/FasL can also promote cell invasion among non-apoptotic cells; ...here, we show that Fas/FasL signaling can promote tumor invasion when apoptosis is compromised. We have developed a recombinant FasL Interfering Protein (FIP) to interfere with Fas signaling in C6 glioma cells expressing both Fas receptor and its ligand. FIP administration did not affect cell viability but impaired cell motility and invasiveness of glioma cells. Blockade of Fas signaling reduced MMP-2 activity in glioma cells, that was associated with down-regulation of MAPK signaling, and AP-1 and NFkappaB-driven transcription. FIP treatment did not affect mmp-2 and mt1-mmp expression but significantly attenuated timp-2 expression and TIMP-2 amount in the culture medium. Studies with pharmacological inhibitors of JNK/c-Jun (SP600125) and NFkappaB (BAY11-7082) signaling pathways demonstrated that timp-2 expression is regulated by NFkappaB transcription factor. Our findings show that non-apoptotic Fas signaling activated in the autocrine manner or through microenvironment derived factors can regulate invasiveness of glioma cells via modulation of MMP-2 activation, likely by controlling TIMP-2 expression.
The past few decades have seen renewed interest in medicinal cannabis or rather cannabinoids – active compounds derived from the Cannabis plant, as well as their endogenous counterparts and a still ...growing set of synthetic derivatives. One of the most extensively studied and promising applications of cannabinoids is their potential use as anti-cancer agents in malignant tumors, such as glioblastomas. The anti-tumor action of cannabinoids is mediated via the CB1 and CB2 cannabinoid receptors. Growing array of data suggest that significant alterations of a balance in the cannabinoid system between the levels of endogenous ligands and their receptors occur along with the malignant transformation in various types of cancer. Increased CB2 receptor expression has been observed in glioblastoma cells, invading microglia/macrophages and endothelial cells of the tumor blood vessels as compared to non-tumor brain samples. Thus, among various approaches to avoid CB1-receptor-mediated psychodysleptic side effects of some cannabinoids, special attention is paid to substances, which selectively stimulate the CB2 receptors, putatively overexpressed in target tumor cells. Induction of cell death by cannabinoid treatment relies on the generation of a pro-apoptotic sphingolipid ceramide and disruption of signaling pathways crucial for regulation of cellular proliferation, differentiation or apoptosis. Increased ceramide levels lead also to ER-stress and autophagy in drug treated glioblastoma cells. Cannabinoids have displayed a great potency in reducing glioma tumor growth in experimental animal models without producing the generalized toxic effects unavoidable with most conventional chemotherapeutic drugs. Apparently their effectiveness in vivo has been attributed to several mechanisms of action. Cannabinoids have recently emerged as compounds that beyond inhibition of tumor cell proliferation and survival impair tumor angiogenesis, invasiveness and even gliomagenesis. The good safety profile observed in a pilot clinical trial, together with remarkable anti-tumor effects reported in preclinical studies may set the basis for further research aimed at better evaluation of the potential anti-cancer activity of cannabinoids. A unique mechanism of cannabinoid action among standard oncology remedies justifies further research on their anti-tumoral properties either alone or in combined therapies.
PDF
