Glial-specific retrovirally mediated gas1 gene expression induces glioma cell apoptosis and inhibits tumor growth in vivo.
We recently reported that the targeted expression of growth arrest specific 1 (Gas1) induces apoptosis in glioma cells. Because the vast majority of gliomas present genetic alterations that reduce their ability to undergo apoptosis, a gene therapy strategy aimed at reinstating apoptotic processes in glioma cells is an interesting approach for the treatment of these tumors. We used a retroviral gene transfer system to transduce C6 glioma cells with a transgene in which the expression of a full-length human gas1 cDNA is under the transcriptional control of a human promoter of the glial fibrillary acidic protein (gfa2). In vitro experiments showed that the retroviral transfer of gas1 significantly reduces the number of viable cells, and induces apoptosis in C6 cells, through the activation of caspase-3. Furthermore, retroviral-mediated transfer of gas1 to gliomas implanted in nude mice induces a significant inhibition of tumor growth, accompanied by increased caspase-3 activation. In the present experiments, we have taken advantage of the property of retrovirus to transfer transgenes exclusively to proliferating cells, together with the use of a glial specific promoter, to selectively target the expression of gas1, a pro-apoptotic gene, to glioma cells.
Zamorano
Absalom
A
Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del IPN, México, 07300, D.F., Mexico.
Mellström
Britt
B
Vergara
Paula
P
Naranjo
José R
JR
Segovia
José
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D005434:Flow Cytometry; D058851:GPI-Linked Proteins; D015870:Gene Expression; D018390:Gene Targeting; D015316:Genetic Therapy; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins / Q000502:physiology*; D009457:Neuroglia / Q000473:pathology* / Q000502:physiology*; D011401:Promoter Regions, Genetic; D051381:Rats; D012190:Retroviridae; D014161:Transduction, Genetic
D018797:Cell Cycle Proteins; C096192:GAS1 protein, human; D058851:GPI-Linked Proteins; C501181:Gas1 protein, rat; D005904:Glial Fibrillary Acidic Protein; D008565:Membrane Proteins; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases