5-aza-2'-deoxycytidine upregulates caspase-9 expression cooperating with p53-induced apoptosis in human lung cancer cells.
Treating lung cancer cell lines using low-dose 5-aza-2'-deoxycytidine (DAC) caused an accumulation of procaspase-9 through mRNA upregulation, but the cells did not undergo apoptosis. However, when cells were treated with DAC and infected with a low dose of a recombinant wild-type p53 adenovirus vector (Ad-p53), a synergistic growth inhibitory effect was observed. Combination treatment induced Apaf-1 and procaspase-9 expression in which cytochrome c releases by Ad-p53 triggered the mitochondrial pathway of apoptosis. Selective blockage of caspase-9 activities by Z-LEHD-FMK completely attenuated DAC-induced enhancement of apoptosis mediated by Ad-p53 infection, and ectopic overexpression of procaspase-9 sensitized cells to Ad-p53-induced apoptosis in p53-null cells. In addition, DAC sensitized lung cancer cells to cisplatin and paclitaxel. Induction of the mitochondrial pathway of apoptosis using a slightly toxic dose of DAC may therefore be a strategy for treating lung cancer, and DAC treatment may have clinical implications when combined with chemotherapy or apoptosis-inducing gene therapy.
Gomyo
Yoshihito
Y
Department of Thoracic and Cardiovascular Surgery and Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
Sasaki
Ji-ichiro
J
Branch
Cynthia
C
Roth
Jack A
JA
Mukhopadhyay
Tapas
T
D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D053453:Caspase 9; D020169:Caspases / Q000235:genetics*; D045744:Cell Line, Tumor; D000077209:Decitabine; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000964:Antimetabolites, Antineoplastic; D016159:Tumor Suppressor Protein p53; D000077209:Decitabine; C506433:CASP9 protein, human; D053453:Caspase 9; D020169:Caspases; D001374:Azacitidine