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Adenovirus-mediated Expression of PML Suppresses Growth and Tumorigenicity of Prostate Cancer Cells¹

Division of Laboratory Medicine [D. H., Z-M. M., X. L., K-S. C.] and the Department of Urology [J-T. H., R-C. P., L. W. K. C.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Our previous studies demonstrated that the promyelocytic leukemia gene, PML, encodes a growth and transformation suppressor. Overexpression of PML inhibits cancer cell growth in vitro and in vivo. In this study, we further explored the possibility of applying PML as a potential agent for developing prostate cancer gene therapy using an adenovirus delivery system. We have constructed and produced the recombinant PML-adenovirus, Ad-PML, in which the full-length PML cDNA is driven by the strong cytomegalovirus promoter. In LNCaP, DU145, and PC-3 prostate cancer cell lines, an infection efficiency of 90% can be achieved at a concentration of 2, 10, and 100 multiplicity of infection (MOI), respectively. Western blotting and immunofluorescence staining demonstrated that the AD-PML-infected cells expressed a high level of PML protein. The protein expression peaked at days 3–4 postinfection, and a detectable level of PML was found at day 18 after viral infection. To test the effect of Ad-PML on the growth of prostate cancer cells, the DU145 and LNCaP cells were infected with 10 and 2 MOI of Ad-PML. We found that the growth rate of the Ad-PML-infected DU145 and LNCaP cells were significantly inhibited. A tumorigenicity test in nude mice showed that the Ad-PML-treated DU145 cells failed to form tumors. Most importantly, direct injection of Ad-PML into DU145-induced tumors was able to repress tumor growth in nude mice by 64%. Taken together, these data indicate that PML is a tumor growth suppressor in prostate cancer and that Ad-PML may be a potential candidate for human prostate cancer therapy.

¹ This study was supported in part by Grant CA55577 from the NIH.

² Present address: Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75235.

³ Present address: Department of Urology, Box 422, Molecular Urology and Therapeutics Program, University of Virginia Health Sciences Center, Charlottesville, VA 22908.

⁴ To whom requests for reprints should be addressed, at Division of Laboratory Medicine, Box 072, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-2581; Fax: (713) 794-1800; E-mail: kchang@notes.mdacc.tmc.edu.

Received 3/ 4/97. Accepted 4/ 2/97.

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