Inactivation of interleukin-8 by aminopeptidase N (CD13)

Kanayama, Naohiro; Kajiwara, Yayoi; Goto, Junko; Maradny, Emad El; Maehara, Kayoko; Andou, Katuaki; Terao, Toshihiko

doi:10.1002/jlb.57.1.129

Cited by 84 publications

(53 citation statements)

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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.

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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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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“…Bestatin is thought to exhibit its antileukemic effects via immunomodulation related to inhibition of aminopeptidases expressed on the cell surface. 8,9 Recently, Kanayama et al 25 reported that IL-8 was degraded by aminopeptidase N and Shibuya et al (unpublished data) found that other cytokines including IL-2, IFN-␥ and G-CSF were degraded by aminopeptidases and bestatin showed extension of the half-lives of the cytokines by inhibiting aminopeptidase N. Immunomodulation by bestatin involves the inhibition of degradation or processing of cytokines by aminopeptidases in addition to the various effects of bestatin on immune cells as reported previously. [2][3][4][5][6][7] On the other hand, Murata et al 26 reported that U937 cells were differentiated to macrophages by bestatin following inhibition of proliferation.…”

Section: Figurementioning

confidence: 99%

Induction of apoptosis by bestatin (ubenimex) in human leukemic cell lines

1999

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We investigated the growth inhibitory activity of bestatin, an inhibitor of aminopeptidase N (CD13), on six human leukemic cell lines. Proliferation of all the cell lines except KG1 was inhibited by bestatin. P39/TSU, HL60 and U937 were highly sensitive, with 50% growth inhibitory concentrations (IC 50 ) close to the maximum serum concentration when bestatin was orally administered at 30 mg in clinical application. All cell lines except for K562 highly expressed CD13, but a clear correlation between the sensitivity to bestatin and expression of CD13 was not observed. Other aminopeptidase inhibitors such as amastatin A, arphamenine B and WM15 antibody showed no growth inhibitory effects. To confirm the growth inhibitory effects of bestatin, we quantitatively examined DNA fragmentation in five bestatin-sensitive cell lines. Bestatin dose-dependently induced DNA fragmentation in those cell lines. In case of U937, bestatin induced DNA fragmentation quantitatively and DNA ladder and enhanced caspase-3 activity. Furthermore, the growth inhibition by bestatin was reduced by the caspase inhibitor Z-Asp-CH 2 -DCB. These results suggested that bestatin exhibits direct antileukemic effects against human leukemic cell lines through the induction of apoptosis.

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“…Although the phagocytic process is finished as early as 5 min after exposure to the bacteria, it seems to be the stimulus for enhanced IL-8 gene expression up to 4 h afterwards [36]. On further incubation, decreased cell viability and perhaps IL-8 degradative processes due to aminopeptidase N might be responsible for the reduced IL-8 levels found in the culture supernates (data not shown) [37].…”

Section: Discussionmentioning

confidence: 93%