Endothelin-receptor antagonists are proapoptotic and antiproliferative in human colon cancer cells

Endothelin (ET)-1 can act as an autocrine/paracrine growth factor or an antiapoptotic factor in human cancers. To study the role of ET-1 in human colon cancer, proliferation and apoptosis of colon carcinoma cells was investigated using human HT-29 and SW480 colon carcinoma cells. ET-1 was secreted by these cells. Treatment of cells with bosentan, a dual ET(A/B)-receptor antagonist, decreased cell number. Inhibition of DNA synthesis by bosentan was observed only in the presence of serum. Exogenously added ET-1 did not increase DNA synthesis in serum-deprived cells. SW480 cells were sensitive and HT-29 cells were resistant to FasL-induced apoptosis. Bosentan sensitised resistant HT-29 cells to FasL-induced, caspase-mediated apoptosis, but not to TNF-alpha-induced apoptosis. Bosentan and/or FasLigand (FasL) did not modulate the expression of caspase-8 or FLIP. Bosentan sensitisation to apoptosis was reversed by low concentrations (10(-13)-10(-10) M), but not by high concentrations (10(-9)-10(-7) M) of ET-1. These results suggest that the binding of ET-1 to high-affinity sites inhibits FasL-induced apoptosis, while the binding of either ET-1 or receptor antagonists to low-affinity sites promotes FasL-induced apoptosis. In conclusion, endothelin signalling pathways do not induce human colon cancer cell proliferation, but are survival signals controling resistance to apoptosis

The combination of DInSAR and facility damage data for the updating of slow-moving landslide inventory maps at medium scale

Abstract. Testing innovative procedures and techniques to update landslide inventory maps is a timely topic widely discussed in the scientific literature. In this regard remote sensing techniques – such as the Synthetic Aperture Radar Differential Interferometry (DInSAR) – can provide a valuable contribution to studies concerning slow-moving landslides in different geological contexts all over the world. In this paper, DInSAR data are firstly analysed via an innovative approach aimed at enhancing both the exploitation and the interpretation of remote sensing information; then, they are complemented with the results of an accurate analysis of survey-recorded damage to facilities due to slow-moving landslides. In particular, after being separately analysed to provide independent landslide movement indicators, the two datasets are combined in a DInSAR-Damage matrix which can be used to update the state of activity of slow-moving landslides. Moreover, together with the information provided by geomorphological maps, the two datasets are proven to be useful in detecting unmapped phenomena. The potentialities of the adopted procedure are tested in an area of southern Italy where slow-moving landslides are widespread and accurately mapped by using geomorphological criteria

Clues of wildfire-induced geotechnical changes in volcanic soils affected by post-fire slope instabilities

Wildfires can significantly affect mountain hillslopes through the combustion of trees and shrubs and changes in soil properties. The type and magnitude of the associated post-fire effects depend on several factors, including fire severity and soil physical-mechanical-hydraulic features that, coupled with climate and topographic conditions, may cause increased runoff, erosion, and slope instability as consequence of intense rainfall. The post-fire response of slopes is highly site-specific. Therefore, in situ surveys and laboratory tests are needed to quantify changes in key soil parameters. The present study documents the post-fire physical and hydromechanical properties of pyroclastic topsoil collected from three test sites that suffered wildfires and rainfall-induced post-fire events in 2019 and 2020 in the Sarno Mountains (Campania Region, southern Italy). The tested pyroclastic soils in burned conditions show (i) no significant changes in grain size distribution, soil organic matter, and specific gravity; (ii) a deterioration in shear strength in terms of decreased soil cohesion caused by the fire-induced weakening of root systems; and (iii) a decrease in hydraulic conductivity. Accordingly, it can be argued that the documented post-fire erosion responses were mainly caused by the reduced cohesion and hydraulic conductivity of the burned topsoil layer, as well as by the loss of vegetation cover and the deposition of fire residues. Although deserving further deepening, this study can represent the necessary background for understanding the initiation mechanism of post-fire erosion processes in the analyzed area and on several natural slopes under similar conditions

Some observations on the relationship of manifest and hidden esca to rainfall

This paper reports observations on the relationship between the yearly incidence of manifest esca (i.e. diseased plants which show foliar symptoms), hidden esca (that which remains asymptomatic throughout a growing season) and rainfall. Data from three vineyards (two in Tuscany and one in Emilia-Romagna, Italy) showed that rainfall in May-July or only in July was inversely related with hidden esca. For two vineyards, TB in Emilia-Romagna and CAR-3 in Tuscany, the spatial pattern of diseased vines in the first year of appearance of the foliar esca symp-toms was also determined. The maps of the vines in these vineyards indicated that diseased plants mostly occurred alone. This suggests that the disease had its origin in infected rooted cuttings or was triggered by inoculum aerially dispersed from distant sources and/or occurring, at least in hypothesis, in the soil

Some Observations on the Relationship of Manifest and Hidden Esca to Rainfall

This paper reports observations on the relationship between the yearly incidence of manifest esca (i.e. diseased plants which show foliar symptoms), hidden esca (that which remains asymptomatic throughout a growing season) and rainfall. Data from three vineyards (two in Tuscany and one in Emilia-Romagna, Italy) showed that rainfall in May–July or only in July was inversely related with hidden esca. For two vineyards, TB in Emilia-Romagna and CAR-3 in Tuscany, the spatial pattern of diseased vines in the first year of appearance of the foliar esca symptoms was also determined. The maps of the vines in these vineyards indicated that diseased plants mostly occurred alone. This suggests that the disease had its origin in infected rooted cuttings or was triggered by inoculum aerially dispersed from distant sources and/or occurring, at least in hypothesis, in the soil

Evaluation of the interaction between TGF beta and nitric oxide in the mechanisms of progression of colon carcinoma

It is recognised that stromal cells determine cancer progression. We have previously shown that active TGFbeta produced by rat colon carcinoma cells modulated NO production in rat endothelial cells. To elucidate the role of TGFbeta and NO in the mechanisms of interaction of colon carcinoma cells with stromal cells and in cancer progression, we transfected REGb cells, a regressive colon carcinoma clone secreting latent TGFbeta, with a cDNA encoding for a constitutively-secreted active TGFbeta. Out of 20 injected rats only one tumour progressed, which was resected and sub-cultured (ReBeta cells). ReBeta cells secreted high levels of active TGFbeta. The adhesive properties of REGb and Rebeta cells to endothelial cells were similar, showing that the secretion of active TGFbeta is not involved in tumour cell adhesion to endothelial cells. ReBeta, but not REGb, cell culture supernatants inhibited cytokine-dependent NO secretion by endothelial cells, but inhibition of NO production was similar in co-cultures of REGb or ReBeta cells with endothelial cells. Therefore, secretion of active TGFbeta regulated endothelial NO synthase activity when tumour cells were distant from, but not in direct contact with, endothelial cells. However, only ReBeta cells inhibited cytokine-dependent secretion of NO in coculture with macrophages, indicating that the active-TGFbeta-NO axis confers an advantage for tumour cells in their interaction with macrophages rather than endothelial cells in cancer progression

Functional Analysis of a Breast Cancer-Associated Mutation in the Intracellular Domain of the Metalloprotease ADAM12

A recently identified breast cancer-associated mutation in the metalloprotease ADAM12 alters a potential dileucine trafficking signal, which could affect protein processing and cellular localization. ADAM12 belongs to the group of A Disintegrin And Metalloproteases (ADAMs), which are typically membrane-associated proteins involved in ectodomain shedding, cell-adhesion, and signaling. ADAM12 as well as several members of the ADAM family are over-expressed in various cancers, correlating with disease stage. Three breast cancer-associated somatic mutations were previously identified in ADAM12, and two of these, one in the metalloprotease domain and another in the disintegrin domain, were investigated and found to result in protein misfolding, retention in the secretory pathway, and failure of zymogen maturation. The third mutation, p.L792F in the ADAM12 cytoplasmic tail, was not investigated, but is potentially significant given its location within a di-leucine motif, which is recognized as a potential cellular trafficking signal. The present study was motivated both by the potential relevance of this documented mutation to cancer, as well as for determining the role of the di-leucine motif in ADAM12 trafficking. Expression of ADAM12 p.L792F in mammalian cells demonstrated quantitatively similar expression levels and zymogen maturation as wild-type (WT) ADAM12, as well as comparable cellular localizations. A cell surface biotinylation assay demonstrated that cell surface levels of ADAM12 WT and ADAM12 p.L792F were similar and that internalization of the mutant occurred at the same rate and extent as for ADAM12 WT. Moreover, functional analysis revealed no differences in cell proliferation or ectodomain shedding of epidermal growth factor (EGF), a known ADAM12 substrate between WT and mutant ADAM12. These data suggest that the ADAM12 p.L792F mutation is unlikely to be a driver (cancer causing)-mutation in breast cancer

PKCα and PKCδ Regulate ADAM17-Mediated Ectodomain Shedding of Heparin Binding-EGF through Separate Pathways

Epidermal growth factor receptor (EGFR) signalling is initiated by the release of EGFR-ligands from membrane-anchored precursors, a process termed ectodomain shedding. This proteolytic event, mainly executed by A Disintegrin And Metalloproteases (ADAMs), is regulated by a number of signal transduction pathways, most notably those involving protein kinase C (PKC). However, the molecular mechanisms of PKC-dependent ectodomain shedding of EGFR-ligands, including the involvement of specific PKC isoforms and possible functional redundancy, are poorly understood. To address this issue, we employed a cell-based system of PMA-induced PKC activation coupled with shedding of heparin binding (HB)-EGF. In agreement with previous studies, we demonstrated that PMA triggers a rapid ADAM17-mediated release of HB-EGF. However, PMA-treatment also results in a protease-independent loss of cell surface HB-EGF. We identified PKCα as the key participant in the activation of ADAM17 and suggest that it acts in parallel with a pathway linking PKCδ and ERK activity. While PKCα specifically regulated PMA-induced shedding, PKCδ and ERK influenced both constitutive and inducible shedding by apparently affecting the level of HB-EGF on the cell surface. Together, these findings indicate the existence of multiple modes of regulation controlling EGFR-ligand availability and subsequent EGFR signal transduction