Oncogene AF1q enhances doxorubicin-induced apoptosis through BAD-mediated mitochondrial apoptotic pathway.
AF1q is an oncogenic factor involved in leukemia development, thyroid tumorigenesis, and breast cancer metastasis. In the present study, AF1q was found to be down-regulated in a doxorubicin-resistant subline of human squamous carcinoma A431 cells. Knockdown of AF1q decreased the apoptosis induced by doxorubicin, Taxol, gamma-radiation, IFN-alpha, and IFN-gamma in A431 cells. On the other hand, overexpression of AF1q increased the doxorubicin-induced apoptosis in A431 cells as well as in HepG2 and HL60 cells. Both exogenous and ectopic expression of AF1q in A431 cells increased the mRNA and protein levels of BAD, a proapoptotic BCL-2 family protein. Gene silencing of BAD by small interfering RNA suppressed the AF1q enhancement of apoptosis, suggesting that BAD is downstream of AF1q in regulation of apoptosis. Furthermore, AF1q enhanced the mitochondrial membrane depolarization, mitochondrial cytochrome c release, and activation of caspase-9 and caspase-3 on doxorubicin treatment. Collectively, AF1q increases doxorubicin-induced apoptosis in cells through activation of BAD-mediated apoptotic pathway. The study provides the first evidence that AF1q plays a critical role in the regulation of apoptosis and drug resistance.
Department of Biochemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong Special Administrative Region, People's Republic of China.
Ngai Na
NN
Co
Wing Pui
WP
Tsang
Timothy W L
TW
Wong
Hoi Hung
HH
Cheung
Tsun Yee
TY
Tsang
Siu Kai
SK
Kong
Tim Tak
TT
Kwok
D017209:Apoptosis / Q000187:drug effects*; D001798:Blood Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics*; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D009857:Oncogenes; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins; D014162:Transfection; D015854:Up-Regulation / Q000187:drug effects; D051025:bcl-Associated Death Protein / Q000235:genetics / Q000378:metabolism*
D001798:Blood Proteins; C091736:MLLT11 protein, human; D009363:Neoplasm Proteins; D016376:Oligonucleotides, Antisense; D011518:Proto-Oncogene Proteins; D051025:bcl-Associated Death Protein; D004317:Doxorubicin