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J. Biol. Chem., Vol. 280, Issue 29, 27173-27178, July 22, 2005

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Association of Plasminogen with Dipeptidyl Peptidase IV and Na⁺/H⁺ Exchanger Isoform NHE3 Regulates Invasion of Human 1-LN Prostate Tumor Cells^*

Mario Gonzalez-Gronow, Uma K. Misra, Govind Gawdi, and Salvatore V. Pizzo

From the Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710

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 (pH_i). 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 pH_i 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 pH_i 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.

Received for publication, January 11, 2005 , and in revised form, May 16, 2005.

^* This work was supported by NHLBI, National Institutes of Health Grant HL-24066 and NCI, National Institutes of Health Grant CA-86344. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed: Dept. of Pathology, Box 3712, Duke University Medical Center, Durham, NC 27710. Tel.: 919-684-8879; Fax: 919-684-8689; E-mail: gonza002{at}mc.duke.edu.

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