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

Cowburn, Andrew S.; Sobolewski, Anastasia; Reed, Ben; Deighton, John; Murray, Joanna; Cadwallader, Karen A.; Bradley, John R.; Chilvers, Edwin R.

doi:10.1074/jbc.m511277200

Cited by 34 publications

(32 citation statements)

References 64 publications

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“…Two of these, annexin A5 and aminopeptidase N, were increased in all uninfected compared to infected mice. Aminopeptidase N extracellular signaling helps to reduce inflammation, and annexin A5 is a known inhibitor of protein kinase C, thus inhibiting apoptosis and degranulation in healthy mice (26,27). This suggests activation of cytotoxic activity from mast cells and granulocytes and activation of inflammation and apoptosis in all infected mice.…”

Section: Resultsmentioning

confidence: 99%

Differences in Host Innate Responses among Coccidioides Isolates in a Murine Model of Pulmonary Coccidioidomycosis

et al. 2015

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e Coccidioides immitis and Coccidioides posadasii are soil-dwelling fungi and the causative agents of coccidioidomycosis, a mycosis endemic to certain semiarid regions in the Americas. The most common route of infection is by inhalation of airborne Coccidioides arthroconidia. Once a susceptible host inhales the conidia, a transition to mature endosporulated spherules can occur within the first 5 days of infection. For this study, we examined the host response in a murine model of coccidioidomycosis during a time period of infection that has not been well characterized. We collected lung tissue and bronchoalveolar lavage fluid (BALF) from BALB/c mice that were infected with a C. immitis pure strain, a C. immitis hybrid strain, or a C. posadasii strain as well as uninfected mice. We compared the host responses to the Coccidioides strains used in this study by assessing the level of transcription of selected cytokine genes in lung tissues and characterized host and fungal proteins present in BALF. Host response varied depending on the Coccidioides strain that was used and did not appear to be overly robust. This study provides a foundation to begin to dissect the host immune response early in infection, to detect abundant Coccidioides proteins, and to develop diagnostics that target these early time points of infection.

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Section: Resultsmentioning

confidence: 99%

Differences in Host Innate Responses among Coccidioides Isolates in a Murine Model of Pulmonary Coccidioidomycosis

et al. 2015

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“…It was also reported that CD13 could block the apoptosis induction by tumor necrosis factor-alpha (26) and enhance sensitivity of tumor cells to cisplatin (27). CD13 was also proved to be involved in cell adhesion (28) as well as in endothelial invasion (29).…”

Section: Discussionmentioning

confidence: 96%

Integrin α6high Cell Population Functions as an Initiator in Tumorigenesis and Relapse of Human Liposarcoma

Wang

et al. 2011

Molecular Cancer Therapeutics

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The relapse and resistance to chemo-and radiotherapy are main problems in the treatment of human liposarcoma. It is important to find a functional marker existing in the liposarcoma cells for targeting. In this article, we established a new sub-cell line SW872-S cells with high tumorigenicity from human liposarcoma SW872 cells by repeated inoculation approach. The characteristic of the sub-cell line is linked to the high levels of integrin a6 on the surface. The integrin a6 high cells show much higher tumor initiation and self-renewal potential in vivo than integrin a6 low cells do. Targeting integrin a6 with its specific short interfering RNA and antibody significantly inhibits the cell adhesion to laminin and the tumor growth in vitro and in vivo, respectively. Interestingly, integrin a6 marks almost all of the surgical biopsy specimens of patients with liposarcoma relapse. Moreover, integrin a6 is found to coexpress with CD13, which might contribute to the antiapoptosis ability of integrin a6 high cells. Consistently, integrin a6 high cells are more sensitive to the CD13 inhibitor bestatin, and 61% of 23 other human tumor cell lines also contain integrin a6 high CD13 high subgroup.These results provide evidence, for the first time, to our knowledge, that integrin a6 and CD13 can serve as functional markers of the tumor-initiation subcell population in human liposarcoma as well as other cancers for therapeutic targeting. Mol Cancer Ther; 10(12); 2276-86. Ó2011 AACR.

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“…Reduction in angiogenesis likely accounts for the tumor growth defect resulting from enzyme inactivation. APN is expressed not only by endothelial cells, but also by pericytes and myeloid and mesenchymal stromal cells (29)(30)(31)(32)(33)(34), all of which are central components of the tumor microenvironment.…”

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.

117

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

Cited by 34 publications

References 64 publications

Differences in Host Innate Responses among Coccidioides Isolates in a Murine Model of Pulmonary Coccidioidomycosis

Differences in Host Innate Responses among Coccidioides Isolates in a Murine Model of Pulmonary Coccidioidomycosis

Integrin α6high Cell Population Functions as an Initiator in Tumorigenesis and Relapse of Human Liposarcoma

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

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