Inhibition of Egr-1 expression reverses transformation of prostate cancer cells in vitro and in vivo.
Transcription factor early growth response-1 (Egr-1) is a crucial regulator of cell growth, differentiation and survival. Several observations suggest that Egr-1 is growth promoting in prostate cancer cells and that blocking its function may impede cancer progression. To test this hypothesis, we developed phosphorothioate antisense oligonucleotides that efficiently inhibit Egr-1 expression without altering the expression of other family members Egr-2, Egr-3 and Egr-4. In TRAMP mouse-derived prostate cancer cell lines, our optimal antisense oligonucleotide decreased the expression of the Egr-1 target gene transforming growth factor-beta1 whereas a control oligonucleotide had no effect, indicating that the antisense blocked Egr-1 function as a transcription factor. The antisense oligonucleotide deregulated cell cycle progression and decreased proliferation of the three TRAMP cell lines by an average of 54+/-3%. Both colony formation and growth in soft agar were inhibited by the antisense oligonucleotide. When TRAMP mice were treated systemically for 10 weeks, the incidence of palpable tumors at 32 weeks of age in untreated mice or mice injected with the control scramble oligonucleotide was 87%, whereas incidence of tumors in antisense-Egr-1-treated mice was significantly reduced to 37% (P=0.026). Thus, Egr-1 plays a functional role in the transformed phenotype and may represent a valid target for prostate cancer therapy.
Baron
Véronique
V
Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, CA 92121, USA. danmercola@skcc.org
De Gregorio
Giorgia
G
Krones-Herzig
Anja
A
Virolle
Thierry
T
Calogero
Antonella
A
Urcis
Rafael
R
Mercola
Dan
D
D000818:Animals; D015153:Blotting, Western; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D002461:Cell Line, Transformed; D002462:Cell Membrane / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D018450:Disease Progression; D051766:Early Growth Response Protein 1; D005434:Flow Cytometry; D017874:Immediate-Early Proteins; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000378:metabolism / Q000494:pharmacology; D010641:Phenotype; D011471:Prostatic Neoplasms / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C486110:Egr1 protein, rat; D017874:Immediate-Early Proteins; D016376:Oligonucleotides, Antisense; D012333:RNA, Messenger; D014157:Transcription Factors; D016212:Transforming Growth Factor beta