Modulation of substance P signaling by dipeptidyl peptidase-IV enzymatic activity in human glioma cell lines.
Dipeptidyl peptidase-IV (DPP-IV, CD26) is a serine protease almost ubiquitously expressed on cell surface and present in body fluids. DPP-IV has been suggested to proteolytically modify a number of biologically active peptides including substance P (SP) and the chemokine stromal cell derived factor-1alpha (SDF-1alpha, CXCL12). SP and SDF-1alpha have been implicated in the regulation of multiple biological processes and also induce responses that may be relevant for glioma progression. Both SP and SDF-1alpha are signaling through cell surface receptors and use intracellular calcium as a second messenger. The effect of DPP-IV on intracellular calcium mobilization mediated by SP and SDF-1alpha was monitored in suspension of wild type U373 and DPP-IV transfected U373DPPIV glioma cells using indicator FURA-2. Nanomolar concentrations of SP triggered a transient dose dependent increase in intracellular calcium rendering the cells refractory to repeated stimulation, while SDF-1 had no measurable effect. SP signaling in DPP-IV overexpressing U373DPPIV cells was not substantially different from that in wild type cells. However, preincubation of SP with the DPP-IV overexpressing cells lead to the loss of its signaling potential, which could be prevented with DPP-IV inhibitors. Taken together, DPP-IV may proteolytically inactivate local mediators involved in gliomagenesis.
Busek
P
P
Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, U Nemocnice 5, Prague, Czech Republic.
Stremeňová
J
J
Krepela
E
E
Sedo
A
A
D001932:Brain Neoplasms / Q000201:enzymology*; D020013:Calcium Signaling / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000235:genetics / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors; D005910:Glioma / Q000201:enzymology*; D006801:Humans; D008239:Lysine / Q000031:analogs & derivatives / Q000494:pharmacology; D015735:Mifepristone / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013373:Substance P / Q000378:metabolism*; D014162:Transfection; D020298:U937 Cells
D054377:Chemokine CXCL12; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009842:Oligopeptides; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors; C110164:lysyl-(Z(nitro))pyrrolidide; D015735:Mifepristone; D013373:Substance P; C041445:diprotin A; C042807:DPP4 protein, human; D018819:Dipeptidyl Peptidase 4; D008239:Lysine