Inhibition of prostate cancer cell growth by human secreted PDZ domain-containing protein 2, a potential autocrine prostate tumor suppressor.
A possible role of the PDZ domain-containing protein 2 (PDZD2) in prostate tumorigenesis has been suggested. Besides, PDZD2 is posttranslationally cleaved by a caspase-dependent mechanism to form a secreted PDZ domain-containing protein 2 (sPDZD2) with unknown functions in humans. In this study, we demonstrate the endogenous expression of PDZD2 and secretion of sPDZD2 in cancerous DU145, PC-3, 22Rv1, LNCaP, and immortalized RWPE-1 prostate epithelial cells. Inhibition of endogenous sPDZD2 production and secretion by DU145, PC-3, 22Rv1, and RWPE-1 cells via the caspase-3 inhibitor Z-DEVD-FMK resulted in increased cell proliferation, which was abrogated by treatment with exogenous recombinant sPDZD2. Whereas sPDZD2-induced antiproliferation in DU145, PC-3, and 22Rv1 cells, it induced apoptosis in LNCaP cells. The data suggest that endogenous sPDZD2, produced by caspase-3-mediated cleavage from PDZD2, may function as a novel autocrine growth suppressor for human prostate cancer cells. The antiproliferative effect of sPDZD2 was apparently mediated through slowing the entry of DU145, PC-3, and 22Rv1 cells into the S phase of the cell cycle. In DU145 cells, this can be attributed to stimulated p53 and p21(CIP1/WAF1) expression by sPDZD2. On the other hand, the apoptotic effect of sPDZD2 on LNCaP cells was apparently mediated via p53-independent Bad stimulation. Together our results indicate the presence of p53-dependent and p53-independent PDZD2/sPDZD2 autocrine growth suppressive signaling pathways in human prostate cancer cells and suggest a novel therapeutic approach of harnessing the latent tumor-suppressive potential of an endogenous autocrine signaling protein like sPDZD2 to inhibit prostate cancer growth.
Tam
C W
CW
Department of Physiology, The University of Hong Kong, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Hong Kong, China.
Cheng
A S
AS
Ma
R Y M
RY
Yao
K-M
KM
Shiu
S Y W
SY
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis / Q000502:physiology*; D017209:Apoptosis; D061945:Caspase Inhibitors; D015815:Cell Adhesion Molecules; D002453:Cell Cycle; D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis; D007659:Ketones / Q000494:pharmacology; D008297:Male; D009363:Neoplasm Proteins / Q000032:analysis / Q000502:physiology*; D011471:Prostatic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D011994:Recombinant Proteins / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D061945:Caspase Inhibitors; D015815:Cell Adhesion Molecules; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004151:Dipeptides; D047908:Intracellular Signaling Peptides and Proteins; D007659:Ketones; D009363:Neoplasm Proteins; C423943:PDZD2 protein, human; D011994:Recombinant Proteins; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; C057383:MDL 201053