Substance P and Bradykinin Are Natural Inhibitors of CD13/Aminopeptidase N

Xu, Yingjiang; Wellner, Daniel; Scheinberg, David A.

doi:10.1006/bbrc.1995.1390

Cited by 51 publications

(32 citation statements)

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“…Natural substrates for CD13 include vasoactive peptides and neuropeptides, including Leu-and Met-enkephalins and the chemokine IL-8 (51). Of note, bradykinin and substance P are also both natural inhibitors of APN activity (52), and this together with our demonstration that PAF enhances APN activity suggest that this molecule is subject to intense and bi-directional regulation. CD13 is expressed on stem cells and during most developmental stages of myeloid cells and is generally considered as a myelomonocytic marker (51).…”

Section: Discussionsupporting

confidence: 54%

Aminopeptidase N (CD13) Regulates Tumor Necrosis Factor-α-induced Apoptosis in Human Neutrophils

Cowburn

Sobolewski

Reed

et al. 2006

Journal of Biological Chemistry

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Neutrophil apoptosis plays a central role in the resolution of granulocytic inflammation. We have shown previously that tumor necrosis factor-␣ (TNF␣) enhances the rate of neutrophil apoptosis at early time points via a mechanism involving both TNF receptor (TNFR) I and TNFRII. Here we reveal a marked but consistent variation in the magnitude of the pro-apoptotic effect of TNF␣ in neutrophils isolated from healthy donors, and we show that inhibition of cell surface aminopeptidase N (APN) using actinonin, bestatin, or inhibitory peptides significantly enhanced the efficacy of TNF␣-induced killing. Notably, an inverse correlation is shown to exist between neutrophil APN activity and the sensitivity of donor cells to TNF␣-induced apoptosis. Inhibition of cell surface APN appears to interfere with the shedding of TNFRI, and as a consequence results in augmented TNF␣-induced apoptosis, cell polarization, and TNF␣-primed, formyl-methionyl-leucyl-phenylalanine-stimulated respiratory burst. Of note, actinonin and bestatin had no effect on TNFRII expression under resting or TNF␣-stimulated conditions and did not alter CXCRI or CXCRII expression. These data suggest significant variation in the activity of APN/CD13 on the cell surface of neutrophils in normal individuals and reveal a novel mechanism whereby APN/CD13 regulates TNF␣-induced apoptosis via inhibition of TNFRI shedding. This has therapeutic relevance for driving neutrophil apoptosis in vivo.

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Section: Discussionsupporting

confidence: 54%

Aminopeptidase N (CD13) Regulates Tumor Necrosis Factor-α-induced Apoptosis in Human Neutrophils

Cowburn

Sobolewski

Reed

et al. 2006

Journal of Biological Chemistry

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“…Identification of APN substrates implicated in tumor growth and metastasis is another required next step. A number of cytokines, growth factors, and extracellular matrix molecules implicated in angiogenesis have been reported as putative APN substrates (46)(47)(48)(49)(50)(51)(52)(53)(54)(55), and testing their possible roles in the models presented here will be the focus of future studies.…”

Section: Discussionmentioning

confidence: 99%

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

Guzman-Rojas

Rangel

Salameh

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

115

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Processes that promote cancer progression such as angiogenesis require a functional interplay between malignant and nonmalignant cells in the tumor microenvironment. The metalloprotease aminopeptidase N (APN; CD13) is often overexpressed in tumor cells and has been implicated in angiogenesis and cancer progression. Our previous studies of APN-null mice revealed impaired neoangiogenesis in model systems without cancer cells and suggested the hypothesis that APN expressed by nonmalignant cells might promote tumor growth. We tested this hypothesis by comparing the effects of APN deficiency in allografted malignant (tumor) and nonmalignant (host) cells on tumor growth and metastasis in APNnull mice. In two independent tumor graft models, APN activity in both the tumors and the host cells cooperate to promote tumor vascularization and growth. Loss of APN expression by the host and/ or the malignant cells also impaired lung metastasis in experimental mouse models. Thus, cooperation in APN expression by both cancer cells and nonmalignant stromal cells within the tumor microenvironment promotes angiogenesis, tumor growth, and metastasis.lung cancer | melanoma | proteolytic activity | shRNA | tumorigenesis A minopeptidase N (APN, CD13; EC 3.4.11.2) is a widely expressed type II membrane-bound metalloprotease (1, 2). It functions in the enzymatic cleavage of peptides, in endocytosis, and as a signaling molecule and has been implicated in the regulation of complex and diverse processes, including cell migration, cell survival, viral uptake, and angiogenesis (3). APN has also been linked specifically to cancer, having been identified as a cellsurface marker for malignant myeloid cells (4-7) and reaching high levels of expression in association with the progression of tumors, including breast, ovarian, and prostate cancer (8-14). Indeed, vascular endothelial growth factor (VEGF), a key angiogenesis regulator, induces the expression of APN at an early stage of tumor growth (15), again highlighting the role of this enzyme in angiogenesis, a process crucial for sustained growth of most solid tumors (16). Studies of bestatin, a CD13 inhibitor and antiangiogenic agent, also suggest that APN enzymatic activity is relevant for tumorigenesis (17,18). Nevertheless, the substrates of APN in the context of angiogenesis are still unknown. The only well-defined substrate is angiotensin III in the renin-angiotensin pathway, in which APN cleaves the NH 2 -terminal arginine residue of angiotensin III to form angiotensin IV. Consistent with several lines of evidence, we have previously identified APN as a target for inhibition of tumor vascularization and growth (18)(19)(20).Tumor growth relies on a complex microenvironment in which malignant cells cooperate with various other cell types: endothelial cells of the blood and lymphatic circulation, mesenchymal stromal cells/cancer-associated fibroblasts, and a variety of bone marrow-derived cells such as myeloid-derived suppressor cells and lymphocytes (21, 22). Some of these cell populations c...

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“…activities with Mca-BK2 and Ala-pNA synthetic substrates (25,26). In 96-well-microplates, the standard reaction consisted of cell membranes in 50 mM Tris⅐HCl, pH 6.5 (hNEP) or pH 7.3 (hAP-N) (200 l final volume).…”

Section: Measurement Of Hnep Ectopeptidase and Hap-n Ectopeptidasementioning

confidence: 99%

Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways

Wisner

Dufour

Messaoudi³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

160

148

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Mammalian zinc ectopeptidases play important roles in turning off neural and hormonal peptide signals at the cell surface, notably those processing sensory information. We report here the discovery of a previously uncharacterized physiological inhibitor of enkephalininactivating zinc ectopeptidases in humans, which we have named Opiorphin. It is a QRFSR peptide that inhibits two enkephalin-catabolizing ectoenzymes, human neutral ecto-endopeptidase, hNEP (EC 3.4.24.11), and human ecto-aminopeptidase, hAP-N (EC 3.4.11.2). Opiorphin displays potent analgesic activity in chemical and mechanical pain models by activating endogenous opioid-dependent transmission. Its function is closely related to the rat sialorphin peptide, which is an inhibitor of pain perception and acts by potentiating endogenous -and ␦-opioid receptor-dependent enkephalinergic pathways. Here we demonstrate the functional specificity in vivo of human Opiorphin. The pain-suppressive potency of Opiorphin is as effective as morphine in the behavioral rat model of acute mechanical pain, the pin-pain test. Thus, our discovery of Opiorphin is extremely exciting from a physiological point of view in the context of endogenous opioidergic pathways, notably in modulating mood-related states and pain sensation. Furthermore, because of its in vivo properties, Opiorphin may have therapeutic implications.dual neutral endopeptidase͞aminopeptidase N inhibitor ͉ human saliva ͉ pain ͉ peptide mediator ͉ enkephalins Z inc metal ectopeptidases control the receptor-dependent activity of neural and hormonal mediators involved in the regulation of important physiological functions in mammals. They are located at the surface of cells in nervous and systemic tissues and catalyze postsecretory processing or metabolism of neuropeptides and regulatory peptides (1, 2). Prominent among these neuronal and͞or hormonal peptide signals are substance P (SP) and enkephalins, which are implicated in the receptor-dependent modulation of behavioral adaptive responses to stressful or threatening environmental stimuli. They notably regulate spinal processing of nociceptive information and analgesic mechanisms, emotional and͞or motivational responses, anxiety, aggression, and neuroimmune inflammatory phenomena (3-6).Because of the physiological importance and the critical role of zinc ectopeptidases in modulating the functional potency of downstream neuronal and hormonal signals, it is essential to focus on what controls their activity and, as a consequence, the overall regulatory cascade. The discovery of upstream regulators of ectopeptidase activity also is exciting from physiopathological and therapeutic points of view because of the potential for developing new candidate drugs. A brain-specific heptapeptide named spinorphin was isolated and characterized from bovine spinal cord based on its inhibitory activity toward enkephalin-degrading ectoenzymes, such as neutral endopeptidase (NEP; EC 3.4.24.11) and aminopeptidase N (AP-N; EC 3.4.11.2) (7,8). In addition, we characterized rat sial...

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Substance P and Bradykinin Are Natural Inhibitors of CD13/Aminopeptidase N

Cited by 51 publications

References 0 publications

Aminopeptidase N (CD13) Regulates Tumor Necrosis Factor-α-induced Apoptosis in Human Neutrophils

Aminopeptidase N (CD13) Regulates Tumor Necrosis Factor-α-induced Apoptosis in Human Neutrophils

Cooperative effects of aminopeptidase N (CD13) expressed by nonmalignant and cancer cells within the tumor microenvironment

Human Opiorphin, a natural antinociceptive modulator of opioid-dependent pathways

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