[Targeting gene expression selectively in cancer cells using the PEG-3 promoter]
>>Published online before print January 12, 2005
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0409141102
Cell Biology
Targeting gene expression selectively in cancer cells by using the progression-elevated gene-3 promoter
( gene therapy | PEG-3 | mda-7/IL-24 | p53 )
Zhao-Zhong Su *, Devanand Sarkar *, Luni Emdad *, Gregory J. Duigou , Charles S. H. Young , Joy Ware , Aaron Randolph ¶, Kristoffer Valerie ¶, and Paul B. Fisher *||
Departments of *Pathology and Microbiology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032; and Departments of Pathology and ¶Radiation Oncology and the Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298
Communicated by George J. Todaro, Targeted Growth, Inc., Seattle, WA, December 8, 2004 (received for review August 6, 2004)
One impediment to effective cancer-specific gene therapy is the rarity of regulatory sequences targeting gene expression selectively in tumor cells. Although many tissue-specific promoters are recognized, few cancer-selective gene promoters are available. Progression-elevated gene-3 (PEG-3) is a rodent gene identified by subtraction hybridization that displays elevated expression as a function of transformation by diversely acting oncogenes, DNA damage, and cancer cell progression. The promoter of PEG-3, PEG-Prom, displays robust expression in a broad spectrum of human cancer cell lines with marginal expression in normal cellular counterparts. Whereas GFP expression, when under the control of a CMV promoter, is detected in both normal and cancer cells, when GFP is expressed under the control of the PEG-Prom, cancer-selective expression is evident. Mutational analysis identifies the AP-1 and PEA-3 transcription factors as primary mediators of selective, cancer-specific expression of the PEG-Prom. Synthesis of apoptosis-inducing genes, under the control of the CMV promoter, inhibits the growth of both normal and cancer cells, whereas PEG-Prom-mediated expression of these genes kills only cancer cells and spares normal cells. The efficacy of the PEG-Prom as part of a cancer gene therapeutic regimen is further documented by in vivo experiments in which PEG-Prom-controlled expression of an apoptosis-inducing gene completely inhibited prostate cancer xenograft growth in nude mice. These compelling observations indicate that the PEG-Prom, with its cancer-specific expression, provides a means of selectively delivering genes to cancer cells, thereby providing a crucial component in developing effective cancer gene therapies.<<
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