This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nanus, D. M. Search for Related Content PubMed PubMed Citation Articles by Nanus, D. M.

Of Peptides and Peptidases

The Role of Cell Surface Peptidases in Cancer

Division of Hematology and Medical Oncology, Department of Medicine, and the Department of Urology, Weill Medical College of Cornell University, New York, New York

Introduction

Therenin-angiotensin system has been studied for over three decades in relation to cardiovascular and renal physiology. Angiotensin II (Ang II), the central product of the renin-angiotensin system, functioning through the Ang II type 1 receptor has been shown to exert numerous effects, including stimulating cell growth, inducing gene expression of various growth factors (i.e., basic fibroblast growth factor, platelet-derived growth factor, and vascular endothelial growth factor) and extracellular matrix components, and activating a variety of intracellular signaling cascades including Janus-activated kinase/signal transducer and activator of transcription, mitogen-activated protein kinase, and epidermal growth factor receptor pathways (1) . These downstream targets of Ang II are reminiscent of those implicated in the malignant phenotype; however, investigation into the potential role of the renin-angiotensin system in cancer has been extremely limited. Recent studies suggest that the Ang II type 1 receptor pathway is proangiogenic in tumors (2, 3, 4) . In the current issue, Watanabe et al. (5) show that Ang II induces an increase in vascular endothelial growth factor expression in endometrial carcinoma cells resulting in increased vascular endothelial cell migration. The involvement of Ang II in the malignant phenotype is not surprising. Other small bioactive peptides (<30 amino acids) such as bombesin and endothelin together with their G protein-coupled receptors participate in autocrine/paracrine stimulation of tumor cell proliferation and migration in many epithelial cancers including breast, colon, lung, pancreatic, and prostate cancers. These peptides and their receptors not only stimulate the synthesis of conventional second messengers but also induce tyrosine phosphorylation signaling cascades (6, 7, 8) .

The enzyme most commonly associated with degradation of Ang II is aminopeptidase A, a cell surface peptidase that removes the NH₂-terminal amino acid aspartyl residue of Ang II to yield angiotensin III (9) . Another angiotensinase, the cytosolic aminopeptidase adipocyte-derived leucine aminopeptidase, was first identified in human placenta and shown recently to be a final processing enzyme of the precursors of MHC class I-resented antigenic peptides (10) . Watanabe et al. (5) report that overexpression of adipocyte-derived leucine aminopeptidase in human endometrial carcinoma cells attenuates the Ang II-mediated stimulation of endothelial cell migration in vitro and inhibits the vascular density of tumors grown in athymic mice, suggesting that adipocyte-derived leucine aminopeptidase in endometrial carcinoma cells regulates the local Ang II concentration, thereby regulating, in part, vascular endothelial growth factor-mediated angiogenesis. Although the role of both adipocyte-derived leucine aminopeptidase and aminopeptidase A in regulating Ang II effects on angiogenesis requires additional investigation, this study highlights the role of small peptides and peptidases in the malignant process.

Limited studies have explored the involvement of cell surface peptidases in the various stages of neoplasia such as tumor initiation and progression and the development of metastatic disease. Cell surface peptidases are the guardians of the cell against small peptides, functioning to control growth and differentiation in normal cells by regulating peptide access to their cell surface receptors. Over 25 cell surface peptidases have been identified in human cell types and tissues, most notably angiotensin-converting enzyme, aminopeptidase A, aminopeptidase N (CD13), dipeptidyl-peptidase IV (CD26), meprin A, and neutral endopeptidase (CD10; Ref. 11 ). These peptidases are integral membrane proteins with their catalytic site exposed to the external cell surface, situated in the membrane with the NH₂ terminus or the COOH-terminus facing extracellularly or through a glycol-phosphatidylinositol anchor. Many also exist as soluble isoforms found in extracellular fluids, although the mechanisms that regulate cell surface peptidase shedding are for the most part unknown. Some were originally identified as hematopoietic cluster of differentiation antigens and as kidney or melanoma differentiation antigens only later to be identified as cell surface enzymes.

The following two basic mechanisms of cell surface peptidase involvement in the malignant process can be predicted: loss of function and gain of function (Fig. 1) . Lost or decreased expression of a peptidase could result in the inability of a cell to inactivate a peptide substrate. This peptide (or peptides) may stimulate cell division, promote cell survival, or affect other processes that contribute to malignancy such as cell migration or invasion. If the cell surface peptidase regulates growth by converting a propeptide to a growth-inhibitory peptide, loss of expression would prevent activation of the growth-inhibitory pathway also resulting in unregulated proliferation. The second mechanism by which a cell surface peptidase could contribute to neoplastic processes, gain of function, would typically result from overexpression of a peptidase by a cell that normally expresses low levels, or peptidase expression in a cell type that normally does not express the enzyme. This resulting increase in catalytic activity could enhance growth by increased conversion of a propeptide to a biologically active form (i.e., endothelin-converting enzyme-1 catalyzes the conversion of the 39-amino acid prohormone peptide big endothelin-1 to the 21-amino acid peptide endothelin-1; Ref. 12 ). Alternatively, overexpression of a cell surface peptidase could result in inactivation of a peptide that normally inhibits proliferation. Alteration in cell surface peptidases could theoretically occur at all stages of malignant transformation.

View larger version (28K): [in this window] [in a new window]   Fig. 1. Cell surface peptidase involvement in the malignant phenotype. Cell surface peptidases are normally found at the cell surface where their catalytic activity regulates access of small peptides to their G protein-coupled receptors (GPCR). 1, loss of expression resulting in increased access of peptides to GPCRs would lead to downstream signaling events such as increased cell growth, cell migration and invasion, and the promotion of cell survival, signalling events that contribute to the malignant phenotype. 2, overexpression of a cell surface peptidase could result in greater inactivation of an inhibitory peptide or increased activation of a stimulatory peptide through conversion from a propeptide to the biologically active form.

In a review published in 1993, Ship and Look suggested that "cutting is the key," or that enzymatic inactivation of peptide substrates accounted for the biological activity of cell surface peptidases (20) . Although this axiom remains true today, it is now clear that cell surface peptidases possess biological activity independent of their enzymatic function. Dipeptidyl-peptidase IV complexes with seprase/fibroblast-activating factor resulting in enhanced negative effects on cell invasiveness (21) , and neutral endopeptidase inhibits focal adhesion kinase phosphorylation and cell migration by a direct interaction of its cytoplasmic domain with Lyn kinase and phosphatidylinositol 3-kinase (22) . It is probable that cell surface peptidases have much in common with integrins, where interactions with other proteins govern their function, and that these interactions result in a variety of properties, including intracellular signaling. Our understanding of the complexities of cell surface peptidases and their role in various cancers is still very limited. As our understanding increases, novel strategies will emerge for improving the diagnosis and treatment of individual malignancies.

FOOTNOTES

Requests for reprints: David M. Nanus, Weill Medical College of Cornell University, 525 East 68th Street, ST-359, New York, New York 10021. Phone: (212) 746-2920; Fax: (212) 746-6645; E-mail: dnanus{at}med.cornell.edu

Received 9/ 8/03; accepted 9/22/03.

REFERENCES

1. Kim S., Iwao H. Molecular and cellular mechanisms of angiotensin II-mediated cardiovascular and renal diseases. Pharmacol. Rev., 52: 11-34, 2000.[Abstract/Free Full Text]
2. Egami K., Murohara T., Shimada T., Sasaki K., Shintani S., Sugaya T., Ishii M., Akagi T., Ikeda H., Matsuishi T., Imaizumi T. Role of host angiotensin II type 1 receptor in tumor angiogenesis and growth. J. Clin. Investig., 142: 67-75, 2003.
3. Fujita M., Hayashi I., Yamashina S., Itoman M., Majima M. Blockade of angiotensin AT1a receptor signaling reduces tumor growth, angiogenesis, and metastasis. Biochem. Biophys. Res. Commun., 294: 441-447, 2002.[CrossRef][Medline]
4. Yoshiji H., Kuriyama S., Kawata M., Yoshii J., Ikenaka Y., Noguchi R., Nakatani T., Tsujinoue H., Fukui H. The angiotensin-I-converting enzyme inhibitor perindopril suppresses tumor growth and angiogenesis: possible role of the vascular endothelial growth factor. Clin. Cancer Res., 7: 1073-1078, 2001.[Abstract/Free Full Text]
5. Watanabe Y., Shibata K., Kikkawa F., Kajiyama H., Ino K., Hattori A., Tsujimoto M., Mizutani S. Adipocyte-derived leucine aminopeptidase (A-LAP) suppresses angiogenesis in human endometrial carcinoma via renin-angiotensin system. Clin. Cancer Res., 9: 6497-6503, 2003.[Abstract/Free Full Text]
6. Rozengurt E. Neuropeptides as growth factors for normal and cancerous cells. Trends Endocrinol. Metab., 13: 128-134, 2002.[CrossRef][Medline]
7. Moody T. W., Chan D., Fahrenkrug J., Jensen R. T. Neuropeptides as autocrine growth factors in cancer cells. Curr. Pharm. Des., 9: 495-509, 2003.[CrossRef][Medline]
8. Nelson J., Bagnato A., Battistini B., Nisen P. The endothelin axis: emerging role in cancer. Nat. Rev. Cancer, 3: 110-116, 2003.[CrossRef][Medline]
9. Nanus D. M., Engelstein D., Gastl G. A., Gluck L., Vidal M. J., Morrison M., Finstad C. L., Bander N. H., Albino A. P. Molecular cloning of the human kidney differentiation antigen gp160: human aminopeptidase A. Proc. Natl. Acad. Sci. USA, 90: 7069-7073, 1993.[Abstract/Free Full Text]
10. Saric T., Chang S. C., Hattori A., York I. A., Markant S., Rock K. L., Tsujimoto M., Goldberg A. L. An IFN--induced aminopeptidase in the ER, ERAP1, trims precursors to MHC class I-presented peptides. Nat. Immunol., 3: 1169-1176, 2002.[CrossRef][Medline]
11. Antczak C., De Meester I., Bauvois B. Ectopeptidases in pathophysiology. Bioessays, 23: 251-260, 2001.[CrossRef][Medline]
12. Turner A. J., Barnes K., Schweizer A., Valdenaire O. Isoforms of endothelin-converting enzyme: why and where?. Trends Pharmacol. Sci., 19: 483-486, 1998.[CrossRef][Medline]
13. Nanus D. M., Shen R., Dai J., Sumitomo M. Neutral endopeptidase and other peptidases such as aminopeptidase A and dipeptidyl peptidase IV in the development and progression of cancer Mizutani S. Turner A. J. Nomura S. Ino K. eds. . Cell-surface aminopeptidases: basic and clinical aspects, 119-128, Elsevier Science Publishers B.V. Amsterdam 2001.
14. Papandreou C. N., Usmani B., Geng Y. P., Bogenrieder T., Freeman R. H., Wilk S., Finstad C. L., Reuter V. E., Powell C. T., Scheinberg D., Magill C., Scher H. I., Albino A. P., Nanus D. M. Neutral endopeptidase 24.11 loss in metastatic human prostate cancer contributes to androgen-independent progression. Nat. Med., 4: 50-57, 1998.[CrossRef][Medline]
15. Dai J., Shen R., Sumitomo M., Goldberg J. S., Geng Y., Navarro D., Xu S., Koutcher J. A., Garzotto M., Powell C. T., Nanus D. M. Tumor suppressive effects of neutral endopeptidase in androgen-independent prostate cancer cells. Clin. Cancer Res., 7: 1370-1377, 2001.[Abstract/Free Full Text]
16. Wesley U. V., Albino A. P., Tiwari S., Houghton A. N. A role for dipeptidyl peptidase IV in suppressing the malignant phenotype of melanocytic cells. J. Exp. Med., 190: 311-322, 1999.[Abstract/Free Full Text]
17. Pethiyagoda C. L., Welch D. R., Fleming T. P. Dipeptidyl peptidase IV (DPPIV) inhibits cellular invasion of melanoma cells. Clin. Exp. Metastasis, 18: 391-400, 2000.[CrossRef][Medline]
18. Kajiyama H., Kikkawa F., Suzuki T., Shibata K., Ino K., Mizutani S. Prolonged survival and decreased invasive activity attributable to dipeptidyl peptidase IV overexpression in ovarian carcinoma. Cancer Res., 62: 2753-2757, 2002.[Abstract/Free Full Text]
19. Mishima Y., Matsumoto-Mishima Y., Terui Y., Katsuyama M., Yamada M., Mori M., Ishizaka Y., Ikeda K., Watanabe J., Mizunuma N., Hayasawa H., Hatake K. Leukemic cell-surface CD13/aminopeptidase N and resistance to apoptosis mediated by endothelial cells. J. Natl. Cancer Inst. (Bethesda), 94: 1020-1028, 2002.[Abstract/Free Full Text]
20. Shipp M. A., Look A. T. Hematopoietic differentiation antigens that are membrane-associated enzymes: cutting is the key!. Blood, 84: 1052-1070, 1993.
21. Chen W. T., Kelly T. Seprase complexes in cellular invasiveness. Cancer Metastisis Rev., 22: 259-269, 2003.[CrossRef][Medline]
22. Sumitomo M., Shen R., Walburg M., Dai J., Geng Y., Navarro D., Boileau G., Papandreou C. N., Giancotti F. G., Knudsen B., Nanus D. M. Neutral endopeptidase inhibits prostate cancer cell migration by blocking focal adhesion kinase signaling. J. Clin. Investig., 106: 1399-1407, 2000.[Medline]

This article has been cited by other articles:

				L. Blanco, G. Larrinaga, I. Perez, J. I. Lopez, J. Gil, E. Agirregoitia, and A. Varona Acid, basic, and neutral peptidases present different profiles in chromophobe renal cell carcinoma and in oncocytoma Am J Physiol Renal Physiol, April 1, 2008; 294(4): F850 - F858. [Abstract] [Full Text] [PDF]

				S.-i. Terawaki, K. Kitano, and T. Hakoshima Structural Basis for Type II Membrane Protein Binding by ERM Proteins Revealed by the Radixin-neutral Endopeptidase 24.11 (NEP) Complex J. Biol. Chem., July 6, 2007; 282(27): 19854 - 19862. [Abstract] [Full Text] [PDF]

				S. Zitzmann, S. Kramer, W. Mier, U. Hebling, A. Altmann, A. Rother, D. Berndorff, M. Eisenhut, and U. Haberkorn Identification and Evaluation of a New Tumor Cell-Binding Peptide, FROP-1 J. Nucl. Med., June 1, 2007; 48(6): 965 - 972. [Abstract] [Full Text] [PDF]

				O. B. Goodman Jr., M. Febbraio, R. Simantov, R. Zheng, R. Shen, R. L. Silverstein, and D. M. Nanus Neprilysin Inhibits Angiogenesis via Proteolysis of Fibroblast Growth Factor-2 J. Biol. Chem., November 3, 2006; 281(44): 33597 - 33605. [Abstract] [Full Text] [PDF]

				L. Chavez-Gutierrez, E. Matta-Camacho, J. Osuna, E. Horjales, P. Joseph-Bravo, B. Maigret, and J.-L. Charli Homology Modeling and Site-directed Mutagenesis of Pyroglutamyl Peptidase II: INSIGHTS INTO OMEGA-VERSUS AMINOPEPTIDASE SPECIFICITY IN THE M1 FAMILY J. Biol. Chem., July 7, 2006; 281(27): 18581 - 18590. [Abstract] [Full Text] [PDF]

				A. Diaz-Perales, V. Quesada, L. M. Sanchez, A. P. Ugalde, M. F. Suarez, A. Fueyo, and C. Lopez-Otin Identification of Human Aminopeptidase O, a Novel Metalloprotease with Structural Similarity to Aminopeptidase B and Leukotriene A4 Hydrolase J. Biol. Chem., April 8, 2005; 280(14): 14310 - 14317. [Abstract] [Full Text] [PDF]

				A. Ghosh, X. Wang, E. Klein, and W. D.W. Heston Novel Role of Prostate-Specific Membrane Antigen in Suppressing Prostate Cancer Invasiveness Cancer Res., February 1, 2005; 65(3): 727 - 731. [Abstract] [Full Text] [PDF]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nanus, D. M. Search for Related Content PubMed PubMed Citation Articles by Nanus, D. M.