Dipeptidyl peptidase-IV inhibits glioma cell growth independent of its enzymatic activity.
Malignant gliomas exhibit abnormal expression of proteolytic enzymes that may participate in the uncontrolled cell proliferation and aberrant interactions with the brain extracellular matrix. The multifunctional membrane bound serine aminopeptidase dipeptidyl peptidase (DPP)-IV has been linked to the development and progression of several malignancies, possibly both through the enzymatic and nonenzymatic mechanisms. In this report we demonstrate the expression of DPP-IV and homologous proteases fibroblast activation protein, DPP8 and DPP9 in primary cell cultures derived from high-grade gliomas, and show that the DPP-IV-like enzymatic activity is negatively associated with their in vitro growth. More importantly, the DPP-IV positive subpopulation isolated from the primary cell cultures using immunomagnetic separation exhibited slower proliferation. Forced expression of the wild as well as the enzymatically inactive mutant DPP-IV in glioma cell lines resulted in their reduced growth, migration and adhesion in vitro, as well as suppressed glioma growth in an orthotopic xenotransplantation mouse model. Microarray analysis of glioma cells with forced DPP-IV expression revealed differential expression of several candidate genes not linked to the tumor suppressive effects of DPP-IV in previous studies. Gene set enrichment analysis of the differentially expressed genes showed overrepresentation of gene ontology terms associated with cell proliferation, cell adhesion and migration. In conclusion, our data show that DPP-IV may interfere with several aspects of the malignant phenotype of glioma cells in great part independent of its enzymatic activity.
Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague 12853, Czech Republic.
Petr
P
Busek
Jarmila
J
Stremenova
Lucie
L
Sromova
Marek
M
Hilser
Eva
E
Balaziova
Dalibor
D
Kosek
Jana
J
Trylcova
Hynek
H
Strnad
Evzen
E
Krepela
Aleksi
A
Sedo
D000818:Animals; D002448:Cell Adhesion; D002453:Cell Cycle; D002465:Cell Movement; D049109:Cell Proliferation; D004150:Dipeptidases / Q000235:genetics / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics* / Q000378:metabolism; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D018189:Immunomagnetic Separation; D008297:Male; D051379:Mice; D009154:Mutation; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000235:genetics*; D014162:Transfection; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D004150:Dipeptidases; C471241:DPP9 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C042807:DPP4 protein, human; C487997:DPP8 protein, human; D018819:Dipeptidyl Peptidase 4