Prostate-specific amplification of expanded polyglutamine expression: a novel approach for cancer gene therapy.
For cancer gene therapy, it is of primary importance to develop a system to sufficiently and selectively express therapeutic genes in cancer cells. In this study, we showed that an approximately 5.3-kb promoter region of the prostate-specific antigen (PSA) gene can replicate the endogenous expression pattern, although its expression is very weak. We then developed a novel two-step transcriptional activation system in which the PSA promoter drives an artificial transcriptional activator, GAL4-VP16 fusion protein, and it in turn activates transgene expressions under the control of GAL4-responsive elements. By using this system, transgene expressions can be greatly augmented while maintaining prostate-specific expression. Finally, we applied this system to drive an expanded polyglutamine, a potent proapoptotic molecule, to induce apoptosis selectively in PSA-positive prostate cancer cells. This novel system would provide an ideal approach for cancer gene therapy applicable not only to prostate cancer but to other cancers as well.
Segawa
T
T
The 4th Department, Osaka Bioscience Institute, Suita, Japan.
Takebayashi
H
H
Kakehi
Y
Y
Yoshida
O
O
Narumiya
S
S
Kakizuka
A
A
D017209:Apoptosis; D005656:Fungal Proteins / Q000235:genetics / Q000378:metabolism; D005784:Gene Amplification; D015316:Genetic Therapy / Q000379:methods*; D006367:HeLa Cells; D006801:Humans; D008297:Male; D010455:Peptides / Q000235:genetics* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011467:Prostate / Q000378:metabolism*; D017430:Prostate-Specific Antigen; D011471:Prostatic Neoplasms / Q000628:therapy*; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D015533:Transcriptional Activation; D019076:Transgenes; D014407:Tumor Cells, Cultured
D005656:Fungal Proteins; C070633:Gal-VP16; D010455:Peptides; D015534:Trans-Activators; C097188:polyglutamine; D017430:Prostate-Specific Antigen