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Caspase-7 Is Activated during Lovastatin-induced Apoptosis of the Prostate Cancer Cell Line LNCaP¹

Departments of Medicine [M. M., G. R. C., S. J. H., S. J. P.] and Cell Biology [M. M., G. R. C.], Veterans Affairs Medical Center and Baylor College of Medicine, Department of Cell Biology [L. S., C. K., L. D.], Texas Biotechnology Corporation, Houston, Texas 77030

The goals of this work were to establish a reproducible and effective model of apoptosis in a cell line derived from advanced prostate cancer and to study the role of the caspase family of proteases in mediating apoptosis in this system. The study involved the use of the prostate cancer cell line LNCaP. Apoptosis was induced using the hydroxymethyl glutaryl CoA reductase inhibitor, lovastatin, and was evaluated by agarose gel electrophoresis of genomic DNA, morphological criteria, and terminal deoxynucleotidyl transferase-mediated nick end labeling. Caspases were studied by catalytic activity, mRNA induction, and protein processing.

Lovastatin (30 µM) was an effective inducer of apoptosis, causing changes that were evident after 48 h and essentially complete after 96–120 h of treatment. These effects were prevented by the simultaneous addition of mevalonate (300 µM) to the culture medium. Lovastatin induced a proteolytic activity that was able to cleave the enzyme poly(ADP-ribose) polymerase and the substrate Z-DEVD-AFC, which is modeled after the P₁-P₄ amino acids of the poly(ADP-ribose) polymerase cleavage site. Caspase-7, but not caspase-3, underwent proteolytic activation during lovastatin-induced apoptosis, an effect prevented by mevalonate. Caspase-7 was the only detected interleukin 1ß converting enzyme family protease with DEVD cleavage activity that exhibited lovastatin-induced mRNA up-regulation. Again, mevalonate blocked this effect. Lovastatin-induced apoptosis also was prevented when the caspase inhibitors Z-DEVD-CH₂F or Z-VAD-CH₂F (100 µM) where added to the medium.

These studies have identified lovastatin as a powerful inducer of apoptosis in the cell line LNCaP. Caspase activation was a necessary event for LNCaP cells to undergo apoptosis during treatment with lovastatin. Of the caspases tested, only caspase-7 underwent proteolytic activation after stimulation with lovastatin. Identification of caspase-7 as a potential mediator of lovastatin-induced apoptosis broadens our knowledge of the molecular events associated with programmed cell death in a cell line derived from prostatic epithelium.

¹ Supported by a Merit Review Grant from the Veterans Administration and a Pilot Project Grant from the Baylor Specialized Program of Research Excellence on Prostate Cancer (to M. M.).

² To whom requests for reprints should be addressed, at Department of Medicine and Cell Biology, Veterans Affairs Medical Center-Baylor College of Medicine, 2002 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 794-7945; E-mail: marcelli@bcm.tmc.edu.

Received 7/14/97. Accepted 10/30/97.

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