Suppression of neuroblastoma growth by dipeptidyl peptidase IV: relevance of chemokine regulation and caspase activation.
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.
Arscott
W T
WT
Department of Microbiology and Molecular Genetics, Vermont Cancer Center, University of Vermont, Burlington, VT 05405, USA.
LaBauve
A E
AE
May
V
V
Wesley
U V
UV
D000818:Animals; D000943:Antigens, Differentiation / Q000096:biosynthesis / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D054377:Chemokine CXCL12 / Q000096:biosynthesis* / Q000235:genetics; D018819:Dipeptidyl Peptidase 4 / Q000096:biosynthesis* / Q000235:genetics; D004789:Enzyme Activation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006133:Growth Substances / Q000096:biosynthesis / Q000235:genetics; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D009432:Neural Crest / Q000201:enzymology / Q000378:metabolism; D009447:Neuroblastoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017207:Rats, Sprague-Dawley; D019718:Receptors, CXCR4 / Q000096:biosynthesis* / Q000235:genetics; D013564:Sympathetic Nervous System / Q000201:enzymology / Q000473:pathology; D014183:Transplantation, Heterologous
D000943:Antigens, Differentiation; D054377:Chemokine CXCL12; C486264:Cxcr4 protein, rat; D006133:Growth Substances; C489787:MAP2 protein, rat; D008869:Microtubule-Associated Proteins; C079240:Mtap2 protein, mouse; D019718:Receptors, CXCR4; D051057:Proto-Oncogene Proteins c-akt; D018819:Dipeptidyl Peptidase 4; D020169:Caspases; D020780:Matrix Metalloproteinase 9