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Research Articles: Therapeutics, Targets, and Development

Prostate-specific membrane antigen associates with anaphase-promoting complex and induces chromosomal instability

¹ Nemours Center for Childhood Cancer Research, Alfred I. DuPont Hospital for Children, Wilmington, Delaware; Departments of ² Pathology and Laboratory Medicine and ³ Hematology/Oncology, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, California; and ⁴ Amgen, Inc., Thousand Oaks, California

Requests for reprints: Ayyappan K. Rajasekaran, Nemours Center for Childhood Cancer Research, Alfred I. DuPont Hospital for Children, Rockland Center I, 1701 Rockland Road, Wilmington, DE 19803. Phone: 302-651-6593; Fax: 302-651-4827. E-mail: araj{at}medsci.udel.edu

Abstract

Prostate-specific membrane antigen (PSMA) is a transmembrane protein highly expressed in advanced and metastatic prostate cancers. The pathologic consequence of elevated PSMA expression in not known. Here, we report that PSMA is localized to a membrane compartment in the vicinity of mitotic spindle poles and associates with the anaphase-promoting complex (APC). PSMA-expressing cells prematurely degrade cyclin B and exit mitosis due to increased APC activity and incomplete inactivation of APC by the spindle assembly checkpoint. Further, expression of PSMA in a karyotypically stable cell line induces aneuploidy. Thus, these findings provide the first evidence that PSMA has a causal role in the induction of aneuploidy and might play an etiologic role in the progression of prostate cancer. [Mol Cancer Ther 2008;7(7):2142–51]

Grant support: Department of Defense grant W81XWH-04-1-0113 and NIH grant DK56216.

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.

Note: S.A. Rajasekaran and J.J. Christiansen contributed equally to this work.

⁵ S.A. Rajasekaran et al., unpublished data.

Received 1/ 4/08; revised 3/ 6/08; accepted 3/ 8/08.