title: Targeting gene expression selectively in cancer cells by using the progression-elevated gene-3 promoter.
abstract: 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.
authors.affiliation: Department of Pathology, College of Physicians and Surgeons, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Zhao-Zhong
authors.initials: ZZ
authors.lastname: Su
authors.forename: Devanand
authors.initials: D
authors.lastname: Sarkar
authors.forename: Luni
authors.initials: L
authors.lastname: Emdad
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Duigou
authors.forename: Charles S H
authors.initials: CS
authors.lastname: Young
authors.forename: Joy
authors.initials: J
authors.lastname: Ware
authors.forename: Aaron
authors.initials: A
authors.lastname: Randolph
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Valerie
authors.forename: Paul B
authors.initials: PB
authors.lastname: Fisher
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics*; D018797:Cell Cycle Proteins; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D006801:Humans; D007378:Interleukins / Q000235:genetics; D008297:Male; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000628:therapy*; D011401:Promoter Regions, Genetic; D054645:Protein Phosphatase 1; D011506:Proteins / Q000235:genetics; D011518:Proto-Oncogene Proteins; D018808:Transcription Factor AP-1 / Q000502:physiology; D014157:Transcription Factors / Q000502:physiology; D000099180:Interleukin-24
chemical_list: D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D007378:Interleukins; D009363:Neoplasm Proteins; D054645:Protein Phosphatase 1; D011506:Proteins; D011518:Proto-Oncogene Proteins; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D000099180:Interleukin-24; C489287:Ppp1r15a protein, rat; C065788:transcription factor PEA3; C087519:PPP1R15A protein, human; C513256:Ppp1r15a protein, mouse