Extra-cellular matrix proteins induce matrix metalloproteinase-1 (MMP-1) activity and increase airway smooth muscle contraction in asthma

Airway remodelling describes the histopathological changes leading to fixed airway obstruction in patients with asthma and includes extra-cellular matrix (ECM) deposition. Matrix metalloproteinase-1 (MMP-1) is present in remodelled airways but its relationship with ECM proteins and the resulting functional consequences are unknown. We used airway smooth muscle cells (ASM) and bronchial biopsies from control donors and patients with asthma to examine the regulation of MMP-1 by ECM in ASM cells and the effect of MMP-1 on ASM contraction. Collagen-I and tenascin-C induced MMP-1 protein expression, which for tenascin-C, was greater in asthma derived ASM cells. Tenascin-C induced MMP-1 expression was dependent on ERK1/2, JNK and p38 MAPK activation and attenuated by function blocking antibodies against the β1 and β3 integrin subunits. Tenascin-C and MMP-1 were not expressed in normal airways but co-localised in the ASM bundles and reticular basement membrane of patients with asthma. Further, ECM from asthma derived ASM cells stimulated MMP-1 expression to a greater degree than ECM from normal ASM. Bradykinin induced contraction of ASM cells seeded in 3D collagen gels was reduced by the MMP inhibitor ilomastat and by siRNA knockdown of MMP-1. In summary, the induction of MMP-1 in ASM cells by tenascin-C occurs in part via integrin mediated MAPK signalling. MMP-1 and tenascin-C are co-localised in the smooth muscle bundles of patients with asthma where this interaction may contribute to enhanced airway contraction. Our findings suggest that ECM changes in airway remodelling via MMP-1 could contribute to an environment promoting greater airway narrowing in response to broncho-constrictor stimuli and worsening asthma symptoms

Matricellular Proteins Produced by Melanocytes and Melanomas: In Search for Functions

Matricellular proteins are modulators of cell-matrix interactions and cellular functions. The group includes thrombospondin, osteopontin, osteonectin/SPARC, tenascin, disintegrins, galectins and CCN proteins. The production of matricellular proteins such as osteopontin, SPARC or tenascin is highly upregulated in melanoma and other tumors but little is known about their functions in tumor growth, survival, and metastasis. The distribution pattern of CCN3 differs from most other matricellular proteins, such that it is produced abundantly by normal melanocytes, but is not significantly expressed in melanoma cells. CCN3 is known to inhibit melanocyte proliferation and stimulate adhesion to collagen type IV, the main component of the basement membrane. CCN3 has a unique role in securing adhesion of melanocytes to the basement membrane distinct from other melanoma-produced matricellular proteins which act as de-adhesive molecules and antagonists of focal adhesion. Qualitative and quantitative changes in matricellular protein expression contribute to melanoma progression similar to the E-cadherin to N-cadherin class switch, allowing melanoma cells to escape from keratinocyte control

Role of Neuropeptides in Sarcomas

Neuropeptides are among the most abundant chemical messengers produced in the brain that can function as neurotransmitters or hormones. Neuropeptides are synthesized and used by a neuron. There are over one hundred known neuropeptides, representing the largest and most diverse class of signaling molecules in the nervous system. Neuropeptides are often co-released with other neuropeptides and neurotransmitters in a single neuron, yielding a multitude of effects. The focus of this review is their role in cancer in general and mainly sarcomas. Neuropeptides and their receptors are no exception when it comes to their pro or antitumorigenic diverse functions defined by cellular and disease content. The molecular targets, pathways, and epigenetic regulation of sarcoma growth by neuropeptides are highlighted to better understand the importance of these molecules and suggest future alternative therapies for this challenging disease with unmet cancer needs

Proline Rich Polypeptide (PRP-1) Increases the Superoxide-Producing and Ferrihemoglobin Reducing Activities of Cytochrome B558 Isoforms from Human Lymphosarcoma Tissue Cells

The two cytochromes (cyt) b558 of acidic nature, one—95–100 kDa and another one, 60–70 kDa were isolated for the first time from the human’s lymphosarcoma tissue cells using gel filtration and ion exchange chromatography. These hemoproteins possess NADPH dependent O2 −-producing and ferrihemoglobin-reducing activities. The incubation of neuropeptide PRP-1 (5 μg) with cytochrome b558, caused elevation of these activities. The gel filtration results indicated possible binding of PRP-1 to these cytochromes b558. PRP-1 activated both NADPH dependent O2 −-producing and ferriHb-reducing activities of the cyt b1 558 and cyt b2 558, obtained from human lymphosarcoma tissue cells. One can assume that PRP-1 associated with cyt b558 on the surface of the tumor cells by increasing both NADPH dependent O2 −-producing and ferriHb-reducing activities of cyt b558, increases the oxidation- reduction status. Changing the oxidation–reduction status and oxygen homeostasis of the tumor cells by PRP-1 can serve as one of the possible explanation of antitumorigenic effect of this cytokine

Antioxidant and Electron Donating Function of Hypothalamic Polypeptides: Galarmin and Gx-NH2

Chemical mechanisms of antioxidant and electron donating function of the hypothalamic proline-rich polypeptides have been clarified on the molecular level. The antioxidant-chelating property of Galarmin and Gx-NH2 was established by their capability to inhibit copper(II) dichloride catalyzed H2O2 decomposition, thus preventing formation of HO• and HOO• radicals. The antiradical activity of Galarmin and Gx-NH2 was determined by their ability to react with 2,2-diphenyl-1-picrylhydrazyl radical applying differential pulse voltammetry and UV–Vis spectrophotometry methods. Galarmin manifest antiradical activity towards 2,2-diphenyl-1-picrylhydrazyl radical, depending on the existence of phenolic OH group in tyrosine residue at the end of the molecule. The presence of antiradical activity and reduction properties of Galarmin are confirmed by the existence of an oxidation specific peak in voltammograms made by differential pulse voltammetry at E ∘ = 0.795 V vs. Ag/Ag+ aq

Dimerization of MLL fusion proteins immortalizes hematopoietic cells.

MLL fusion proteins are leukemogenic, but their mechanism is unclear. Induced dimerization of a truncated MLL immortalizes bone marrow and imposes a reversible block on myeloid differentiation associated with upregulation of Hox a7, a9, and Meis1. Both dimerized MLL and exon-duplicated MLL are potent transcriptional activators, suggesting a link between dimerization and partial tandem duplication of DNA binding domains of MLL. Dimerized MLL binds with higher affinity than undimerized MLL to a CpG island within the Hox a9 locus. However, MLL-AF9 is not dimerized in vivo. The data support a model in which either MLL dimerization/exon duplication or fusion to a transcriptional activator results in Hox gene upregulation and ultimately transformation