GSH depletion enhances adenoviral bax-induced apoptosis in lung cancer cells.
The utility of dominant acting proapoptotic molecules to induce cell death in cancer cells is being evaluated in preclinical studies and clinical trials. We recently developed a binary adenoviral expression system to enable the efficient gene transfer of Bax and other proapoptotic molecules. Using this system, overexpression of Bax protein in four non-small-cell lung cancer (NSCLC) cell lines, H1299, A549, H226 and H322, was evaluated. The H322 line exhibited significant resistance to Bax-induced cell death compared to the other cell lines. H322 cells had the highest level of glutathione (GSH). GSH levels were significantly decreased following buthionine sulfoximine treatment and this coincided with enhanced apoptosis induction by Ad-Bax in H322 cells. GSH depletion enhanced Bax protein translocation to mitochondrial membranes. These findings suggest that the redox status may be a determinant of Bax-mediated cell death and that manipulation of intracellular thiols may sensitize cells to apoptosis by facilitating Bax insertion into mitochondrial membranes.
Honda
Tsuyoshi
T
Department of Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA.
Coppola
Simona
S
Ghibelli
Lina
L
Cho
Song H
SH
Kagawa
Shunsuke
S
Spurgers
Kevin B
KB
Brisbay
Shawn M
SM
Roth
Jack A
JA
Meyn
Raymond E
RE
Fang
Bingliang
B
McDonnell
Timothy J
TJ
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000187:drug effects; D001681:Biological Assay; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D045304:Cytochromes c / Q000378:metabolism; D003851:Deoxyribonucleases / Q000378:metabolism; D018014:Gene Transfer Techniques; D019254:Genes, bcl-2 / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D005978:Glutathione / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D008928:Mitochondria / Q000378:metabolism; D010084:Oxidation-Reduction; D000075223:Poly-ADP-Ribose Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics* / Q000378:metabolism; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein
C494826:BAX protein, human; C494811:BCL2L1 protein, human; D000075223:Poly-ADP-Ribose Binding Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; D019328:Buthionine Sulfoximine; D045304:Cytochromes c; C113696:DFFB protein, human; D003851:Deoxyribonucleases; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D005978:Glutathione