Abrogation of cyclin D1 expression predisposes lung cancer cells to serum deprivation-induced apoptosis.
Cyclin D1 antisense (D1AS)-transfected lung epithelial cell lines were serum deprived and then analyzed for three hallmarks of apoptosis: appearance of single-strand DNA breaks, alteration of apoptosis-related protein expression, and induction of chromatin condensation. Single-strand DNA breaks appeared at significant levels 24 h after serum deprivation, whereas induction of chromatin condensation was observed after 72 h. The antioxidants dimethyl sulfoxide, ascorbate, and glutathione, as well as insulin-like growth factor-I, inhibited induction of DNA damage in this assay. Additionally, proliferating cell nuclear antigen expression is completely suppressed in the D1AS cells, indicating a mechanism to explain the reduced capacity for DNA repair. Increased expression of cyclin D1, which is a common lesion in lung cancer, may thus prevent induction of apoptosis in an oxidizing and growth factor-poor environment. Reducing cyclin D1 expression in lung cancer cells by expression of D1AS RNA disrupted these protective pathways.
Driscoll
B
B
Department of Surgery and Cell and Developmental Biology Program, Childrens Hospital Los Angeles Research Institute, University of Southern California School of Medicine, Los Angeles, California 90027, USA.
Buckley
S
S
Barsky
L
L
Weinberg
K
K
Anderson
K D
KD
Warburton
D
D
D000975:Antioxidants / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001205:Ascorbic Acid / Q000494:pharmacology; D016895:Culture Media, Serum-Free; D019938:Cyclin D1 / Q000235:genetics* / Q000502:physiology; D004249:DNA Damage; D004260:DNA Repair / Q000187:drug effects; D004121:Dimethyl Sulfoxide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D005978:Glutathione / Q000494:pharmacology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008175:Lung Neoplasms; D020319:Oligodeoxyribonucleotides, Antisense / Q000494:pharmacology*; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D014407:Tumor Cells, Cultured
D000975:Antioxidants; D016895:Culture Media, Serum-Free; D020319:Oligodeoxyribonucleotides, Antisense; D018809:Proliferating Cell Nuclear Antigen; D019938:Cyclin D1; D007334:Insulin-Like Growth Factor I; D005978:Glutathione; D001205:Ascorbic Acid; D004121:Dimethyl Sulfoxide