Association of plasminogen with dipeptidyl peptidase IV and Na+/H+ exchanger isoform NHE3 regulates invasion of human 1-LN prostate tumor cells.
Binding of plasminogen type II (Pg 2) to dipeptidyl peptidase IV (DPP IV) on the surface of the highly invasive 1-LN human prostate tumor cell line induces an intracellular Ca2+ ([Ca2+]i) signaling cascade accompanied by a rise in intracellular pH (pHi). In endothelial cells, Pg 2 regulates intracellular pH via Na+/H+ exchange (NHE) antiporters; however, this mechanism has not been demonstrated in any other cell type including prostate cancer cells. Because the Pg 2 receptor DPP IV is associated with NHE3 in kidney cell plasma membranes, we investigated a similar association in 1-LN human prostate cancer cells and a mechanistic explanation for changes in [Ca2+]i or pHi induced by Pg 2 in these cells. Our results suggest that the signaling cascade initiated by Pg 2 and its receptor proceeds via activation of phospholipase C, which promotes formation of inositol 3,4,5-trisphosphate, an inducer of Ca2+ release from endoplasmic reticulum stores. Furthermore, our results suggest that Pg 2 may regulate pHi via an association with NHE3 linked to DPP IV in these cells. These associations suggest that Pg has the potential to simultaneously regulate calcium signaling pathways and Na+/H+ exchanges necessary for tumor cell proliferation and invasiveness.
Gonzalez-Gronow
Mario
M
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA. gonza002@mc.duke.edu
Misra
Uma K
UK
Gawdi
Govind
G
Pizzo
Salvatore V
SV
D000595:Amino Acid Sequence; D020013:Calcium Signaling; D045744:Cell Line, Tumor; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism* / Q000502:physiology; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness / Q000473:pathology*; D010958:Plasminogen / Q000378:metabolism* / Q000502:physiology; D011471:Prostatic Neoplasms / Q000473:pathology*; D018892:Proton-Motive Force; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers / Q000378:metabolism* / Q000502:physiology; D010738:Type C Phospholipases / Q000378:metabolism
C000613385:SLC9A3 protein, human; D000074083:Sodium-Hydrogen Exchanger 3; D017923:Sodium-Hydrogen Exchangers; D010958:Plasminogen; D010738:Type C Phospholipases; D018819:Dipeptidyl Peptidase 4