Extracellular signal-regulated kinase activation and Bcl-2 downregulation mediate apoptosis after gemcitabine treatment partly via a p53-independent pathway.
Gemcitabine is a promising compound for the treatment of human lung cancer. Although apoptosis has been shown to play a role in certain cell types with gemcitabine, the steps leading to cell death after the drug-target interaction are not well understood. We studied the molecular mechanisms of gemcitabine-induced apoptosis and determined the role of p53 function on the cytotoxic effects of gemcitabine in human nonsmall cell lung cancer (NSCLC) H1299 and H1299/p53 cells. Here, we found that gemcitabine induced an apoptotic cell death via a Bcl-2-dependent caspase-9 activation pathway. Moreover, phosphorylated activation of extracellular signal-regulated kinase (ERK) was observed upon gemcitabine treatment. Genetical or pharmacological inhibition of ERK activation markedly blocked gemcitabine-induced cell death. Furthermore, inactivation of Akt was also involved in this event. Taken together, our observations indicate that ERK activation and Akt inactivation mediated gemcitabine-induced apoptosis independently of p53 in human NSCLC H1299 cells.
Division of Chest Medicine, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan. august@vghtc.gov.tw
Gee-Chen
GC
Chang
Shih-Lan
SL
Hsu
Jia-Rong
JR
Tsai
Wen-Jun
WJ
Wu
Chih-Yi
CY
Chen
Gwo-Tarng
GT
Sheu
D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D019254:Genes, bcl-2 / Q000187:drug effects* / Q000502:physiology; D016158:Genes, p53 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000093542:Gemcitabine
D003841:Deoxycytidine; D048049:Extracellular Signal-Regulated MAP Kinases; D000093542:Gemcitabine