Suppression of Neuroblastoma Growth by Dipeptidyl Peptidase IV: Relevance of Chemokine Regulation and Caspase Activation

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2008 Nov 4

PMID 18978811

Citations 28

Authors

W T Arscott

A E LaBauve

V May

U V Wesley

Affiliations

Soon will be listed here.

Abstract

Imbalanced protease expression and activities may contribute to the development of cancers, including neuroblastoma (NB). NB is a fatal childhood cancer of the sympathetic nervous system that frequently overexpresses mitogenic peptides, chemokines and their receptors. Dipeptidyl peptidase IV (DPPIV), a cell surface serine protease, inactivates or degrades some of these bioactive peptides and chemokines, thereby regulating cell proliferation and survival. Our studies show that DPPIV is expressed in normal neural crest-derived structures, including superior cervical and dorsal root ganglion cells, sciatic nerve, and in adrenal glands, but its expression is greatly decreased or lost in cells derived from NB, their malignant counterpart. Restoration of DPPIV expression in NB cells led to their differentiation in association with increased expression of the neural marker MAP2 and decreased expression of chemokines, including stromal-derived factor 1 (SDF1) and its receptor CXCR4. Furthermore, DPPIV promoted apoptosis, and inhibited SDF1-mediated in vitro cell migration and angiogenic potential. These changes were accompanied by caspase activation and decreased levels of phospho-Akt and MMP9 activity, which are downstream effectors of SDF1-CXCR4 signaling. Importantly, DPPIV suppressed the tumorigenic potential of NB cells in a xenotransplantation mouse model. These data support a potential role for DPPIV in inhibiting NB growth and progression.

Citing Articles

Neurological Sequelae of Post-COVID-19 Fatigue: A Narrative Review of Dipeptidyl Peptidase IV-Mediated Cerebrovascular Complications.

Che Mohd Nassir C, Che Ramli M, Jaffer U, Abdul Hamid H, Mehat M, Ghazali M Curr Issues Mol Biol. 2024; 46(12):13565-13582.

PMID: 39727939 PMC: 11727395. DOI: 10.3390/cimb46120811.

Sitagliptin elevates plasma and CSF incretin levels following oral administration to nonhuman primates: relevance for neurodegenerative disorders.

Li Y, Vaughan K, Wang Y, Yu S, Bae E, Tamargo I Geroscience. 2024; 46(5):4397-4414.

PMID: 38532069 PMC: 11335710. DOI: 10.1007/s11357-024-01120-4.

Gene Networks of Hyperglycemia, Diabetic Complications, and Human Proteins Targeted by SARS-CoV-2: What Is the Molecular Basis for Comorbidity?.

Saik O, Klimontov V Int J Mol Sci. 2022; 23(13).

PMID: 35806251 PMC: 9266766. DOI: 10.3390/ijms23137247.

Does DPP-IV Inhibition Offer New Avenues for Therapeutic Intervention in Malignant Disease?.

Busek P, Duke-Cohan J, Sedo A Cancers (Basel). 2022; 14(9).

PMID: 35565202 PMC: 9103952. DOI: 10.3390/cancers14092072.

The Serine Protease CD26/DPP4 in Non-Transformed and Malignant T Cells.

Chitadze G, Wehkamp U, Janssen O, Bruggemann M, Lettau M Cancers (Basel). 2021; 13(23).

PMID: 34885056 PMC: 8657226. DOI: 10.3390/cancers13235947.

References

Carl-McGrath S, Lendeckel U, Ebert M, Rocken C . Ectopeptidases in tumour biology: a review. Histol Histopathol. 2006; 21(12):1339-53. DOI: 10.14670/HH-21.1339. View

Kajiyama H, Shibata K, Terauchi M, Ino K, Nawa A, Kikkawa F . Involvement of DPPIV/CD26 in epithelial morphology and suppressed invasive ability in ovarian carcinoma cells. Ann N Y Acad Sci. 2006; 1086:233-40. DOI: 10.1196/annals.1377.007. View

Golubkov V, Strongin A . Proteolysis-driven oncogenesis. Cell Cycle. 2007; 6(2):147-50. DOI: 10.4161/cc.6.2.3706. View

Guyon A, Nahon J . Multiple actions of the chemokine stromal cell-derived factor-1alpha on neuronal activity. J Mol Endocrinol. 2007; 38(3):365-76. DOI: 10.1677/JME-06-0013. View

Maris J, Hogarty M, Bagatell R, Cohn S . Neuroblastoma. Lancet. 2007; 369(9579):2106-20. DOI: 10.1016/S0140-6736(07)60983-0. View

Castel V, Grau E, Noguera R, Martinez F . Molecular biology of neuroblastoma. Clin Transl Oncol. 2007; 9(8):478-83. DOI: 10.1007/s12094-007-0091-7. View

Bonfil R, Chinni S, Fridman R, Kim H, Cher M . Proteases, growth factors, chemokines, and the microenvironment in prostate cancer bone metastasis. Urol Oncol. 2007; 25(5):407-11. DOI: 10.1016/j.urolonc.2007.05.008. View

Raman D, Baugher P, Thu Y, Richmond A . Role of chemokines in tumor growth. Cancer Lett. 2007; 256(2):137-65. PMC: 2065851. DOI: 10.1016/j.canlet.2007.05.013. View

Havre P, Abe M, Urasaki Y, Ohnuma K, Morimoto C, Dang N . The role of CD26/dipeptidyl peptidase IV in cancer. Front Biosci. 2007; 13:1634-45. DOI: 10.2741/2787. View

10.

Singh S, Sadanandam A, Singh R . Chemokines in tumor angiogenesis and metastasis. Cancer Metastasis Rev. 2007; 26(3-4):453-67. PMC: 4237067. DOI: 10.1007/s10555-007-9068-9. View

11.

Li Z, Thiele C . Targeting Akt to increase the sensitivity of neuroblastoma to chemotherapy: lessons learned from the brain-derived neurotrophic factor/TrkB signal transduction pathway. Expert Opin Ther Targets. 2007; 11(12):1611-21. DOI: 10.1517/14728222.11.12.1611. View

12.

Airoldi I, Cocco C, Morandi F, Prigione I, Pistoia V . CXCR5 may be involved in the attraction of human metastatic neuroblastoma cells to the bone marrow. Cancer Immunol Immunother. 2007; 57(4):541-8. PMC: 11030188. DOI: 10.1007/s00262-007-0392-2. View

13.

Matthay K . Chemotherapy for neuroblastoma: does it hit the target?. Lancet Oncol. 2008; 9(3):195-6. DOI: 10.1016/S1470-2045(08)70046-9. View

14.

Maris J, Woods W . Screening for neuroblastoma: a resurrected idea?. Lancet. 2008; 371(9619):1142-3. DOI: 10.1016/S0140-6736(08)60500-0. View

15.

Mentlein R . Dipeptidyl-peptidase IV (CD26)--role in the inactivation of regulatory peptides. Regul Pept. 1999; 85(1):9-24. DOI: 10.1016/s0167-0115(99)00089-0. View

16.

Eggert A, Ikegaki N, Kwiatkowski J, Zhao H, Brodeur G, Himelstein B . High-level expression of angiogenic factors is associated with advanced tumor stage in human neuroblastomas. Clin Cancer Res. 2000; 6(5):1900-8. View

17.

Dobers J, Grams S, REUTTER W, Fan H . Roles of cysteines in rat dipeptidyl peptidase IV/CD26 in processing and proteolytic activity. Eur J Biochem. 2000; 267(16):5093-100. DOI: 10.1046/j.1432-1327.2000.01571.x. View

18.

Durinx C, Lambeir A, Bosmans E, Falmagne J, Berghmans R, Haemers A . Molecular characterization of dipeptidyl peptidase activity in serum: soluble CD26/dipeptidyl peptidase IV is responsible for the release of X-Pro dipeptides. Eur J Biochem. 2000; 267(17):5608-13. DOI: 10.1046/j.1432-1327.2000.01634.x. View

19.

Gerard C, Rollins B . Chemokines and disease. Nat Immunol. 2001; 2(2):108-15. DOI: 10.1038/84209. View

20.

Scharpe S, De Meester I . Peptide truncation by dipeptidyl peptidase IV: a new pathway for drug discovery?. Verh K Acad Geneeskd Belg. 2001; 63(1):5-32; discussion 32-3. View