Novel role of prostate-specific membrane antigen in suppressing prostate cancer invasiveness.

Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein, is overexpressed in prostate cancer. PSMA is a unique cell surface marker, negatively regulated by androgen and extensively used for imaging of hormone refractory carcinomas and metastatic foci. PSMA is a carboxypeptidase with two important enzymatic functions, namely, folate hydrolase and NAALADase. PSMA also exhibits an endocytic function, in which it spontaneously recycles through endocytic vesicles. PSMA is overexpressed at various stages of prostate cancer, including androgen-sensitive and -independent disease, increased in expression with early relapse after therapy. We have used in vitro invasion assays to explore the possible role of PSMA in the metastasis of prostate cancer cells. Androgen-dependent prostate cancer lines, which express PSMA endogenously (e.g., LNCaP, MDA PCa2b, and CWR22Rv1) are less invasive compared with androgen-independent PC3 or DU145 cells, neither of which expresses PSMA. Ectopic expression of PSMA in PC3 cells reduced the invasiveness of these cells, suggesting that this reduction in the invasion capability of PSMA-expressing cells is due to PSMA expression and not to intrinsic properties of different prostate cancer cell lines. Furthermore, knockdown of PSMA expression increased invasiveness of LNCaP cells by 5-fold. Finally, expression of PSMA mutants lacking carboxypeptidase activity reduced the impact of PSMA expression on invasiveness. Thus, it seems that the enzymatic activity is associated with the effect of PSMA on invasiveness.

[1]  Prabhjot Kaur,et al.  Correlation of primary tumor prostate-specific membrane antigen expression with disease recurrence in prostate cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[2]  J. Coyle,et al.  Site-directed mutagenesis of predicted active site residues in glutamate carboxypeptidase II. , 1999, Molecular pharmacology.

[3]  B. Suffoletto,et al.  Prostate-specific membrane antigen: a novel folate hydrolase in human prostatic carcinoma cells. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[4]  W. Heston,et al.  Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer , 2004, Journal of cellular biochemistry.

[5]  A. Jemal,et al.  Cancer Statistics, 2004 , 2004, CA: a cancer journal for clinicians.

[6]  N. Bander,et al.  Prostate-specific membrane antigen association with filamin A modulates its internalization and NAALADase activity. , 2003, Cancer research.

[7]  J. Bowie,et al.  A novel cytoplasmic tail MXXXL motif mediates the internalization of prostate-specific membrane antigen. , 2003, Molecular biology of the cell.

[8]  N. Dubrawsky.  Cancer statistics , 1989, CA: a cancer journal for clinicians.

[9]  W. Fair,et al.  Evaluation of the tetracycline‐repressible transactivator system for inducible gene expression in human prostate cancer cell lines , 1997, The Prostate.

[10]  J. Konvalinka,et al.  Substrate specificity, inhibition and enzymological analysis of recombinant human glutamate carboxypeptidase II , 2002, Journal of neurochemistry.

[11]  N. Bander,et al.  Constitutive and antibody-induced internalization of prostate-specific membrane antigen. , 1998, Cancer research.

[12]  J. Coyle,et al.  Hydrolysis of the brain dipeptide N-acetyl-L-aspartyl-L-glutamate. Identification and characterization of a novel N-acetylated alpha-linked acidic dipeptidase activity from rat brain. , 1987, The Journal of biological chemistry.

[13]  L. Foroni,et al.  A Fluorescence in Situ Hybridization Map of 6q Deletions in Acute Lymphocytic Leukemia , 2004, Cancer Research.

[14]  Hiroshi Ohno,et al.  Cytoplasmic tail–dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity , 2001, The Journal of cell biology.

[15]  Y Iwamoto,et al.  A rapid in vitro assay for quantitating the invasive potential of tumor cells. , 1987, Cancer research.

[16]  Bernhard O. Palsson,et al.  Cancer cell lines , 1999 .

[17]  D. Nanus.  Of peptides and peptidases: the role of cell surface peptidases in cancer. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[18]  W. Fair,et al.  Molecular cloning of a complementary DNA encoding a prostate-specific membrane antigen. , 1993, Cancer research.

[19]  E. Klein,et al.  Expression of metabotropic glutamate receptors in human prostate cancers and its potential signaling through prostate specific membrane antigen , 2004 .

[20]  N. Bander,et al.  Cancer patient T cells genetically targeted to prostate-specific membrane antigen specifically lyse prostate cancer cells and release cytokines in response to prostate-specific membrane antigen. , 1999, Neoplasia.

[21]  W. Heston,et al.  Effect of carbohydrate moieties on the folate hydrolysis activity of the prostate specific membrane antigen , 2003, The Prostate.

[22]  D. Bostwick,et al.  Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases. , 1998, Urology.