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Prevention of Cell Death Induced by Tumor Necrosis Factor in LNCaP Cells by Overexpression of Sulfated Glycoprotein-2 (Clusterin)¹

Department of Urology, Northwestern University Medical School, Chicago, Illinois 60611 [J. A. S., J. M. K., C. L.]; Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285 [D. M. S.]; Department of Urology, Columbia University School of Medicine, New York, New York 10021[T. R., R. B.]; and Department of Biochemistry and Biophysics, Washington State University, Pullman, Washington 99164 [M. D. G., S. R. S.]

Sulfated glycoprotein-2 (SGP-2) expression has been associated with programmed cell death in the prostate, but its exact role remains unclear. The present study was carried out in an attempt to establish the function of SGP-2 in programmed cell death using tumor necrosis factor (TNF)-induced cytotoxicity in LNCaP cells as the model system. LNCaP is an androgen-sensitive, human prostatic cancer cell line that responds to TNF in culture by undergoing programmed cell death, as determined by the loss of cell number, failure to exclude trypan blue, detection of DNA fragmentation, and increased release of previously incorporated [³H]thymidine. Immunocytochemical staining for SGP-2 was weak but evident in LNCaP cells. Following treatment with TNF, there was a time-dependent increase in SGP-2 staining, the intensity of which peaked at 2 h and declined thereafter. SGP-2 staining in LNCaP cells was undetectable prior to the onset of DNA fragmentation at 6 h of TNF treatment. This observation indicated that TNF-induced cell death in LNCaP cells was characterized by an initial transient elevation of SGP-2, followed by a period of SGP-2 depletion that preceded cell death. Transfection of LNCaP with a 21-base oligonucleotide antisense to SGP-2 resulted in a significant increase in cell death that was sequence specific and was accompanied by a reduction in SGP2 biosynthesis. These findings supported the concept that SGP-2 depletion, rather than its expression, was associated with cell death. Finally, stable transfection and subsequent overexpression of SGP-2 in LNCaP cells resulted in resistance to the cytotoxic effect of TNF. These results have provided evidence to indicate that SGP-2 plays a role in the protection of TNF-induced cell death in LNCaP cells.

¹ This work was supported in part by NIH Grants DK-39250, DK-43541, HD-28048, and CA-60553 (to C. L.), CA-47848 (to R. B.), and HD-30692 (to M. D. G.), fellowships from the American Foundation for Urologic Disease and the William O. Jeffrey III Fellowship for Prostate Cancer Research (to J. A. S.), and funds supporting the Rogovin-Crown Uro-Oncology Research Laboratory at Northwestern University Medical School.

² To whom requests for reprints should be addressed, at Department of Urology, Northwestern University Medical School, 303 E. Chicago Ave., Chicago, IL 60611.

Received 11/14/94. Accepted 3/29/95.

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