Involvement of p21Waf1 in mediating inhibition of paclitaxel-induced apoptosis by epidermal growth factor in MDA-MB-468 human breast cancer cells.
Paclitaxel (Taxol) is currently one of the most widely used anti-cancer drugs for human breast cancer. In this study, we investigated how epidermal growth factor (EGF) modulated paclitaxel-induced apoptosis in MDA-MB-468 human breast adenocarcinoma cells. Pulse-exposure of the cells to paclitaxel resulted in cell death through apoptosis. When EGF was present during the post-paclitaxel culture period, this paclitaxel-induced apoptosis was inhibited in an EGF dose-dependent manner. The induction of apoptosis by paclitaxel was accompanied by an elevated level of p34cdc2 kinase activity, which was inhibited in the presence of EGF during the post-paclitaxel culture period. Exposure of MDA-MB-468 cells to EGF induced expression of the cyclin-dependent kinase inhibitor p21Waf1. Incubation of paclitaxel-treated MDA-MB-468 cell extracts with EGF-treated MDA-MB-468 cell extract, which exhibited elevation of p34cdc2 activity, inhibited the kinase activity. This inhibition was not observed with p21Waf1-immunodepleted EGF-treated cell extract. Transfection of the cells with p21Waf1 antisense oligonucleotide abolished the induction of p21Waf1 and also significantly reduced inhibition by EGF of paclitaxel-induced apoptosis. These studies demonstrate that p21Waf1 plays a key role in the inhibition of paclitaxel-induced apoptosis by EGF in MDA-MB-468 cells.
Fang
M
M
Department of Clinical Investigation, University of Texas M.D. Anderson Cancer Center, Houston, USA.
Liu
B
B
Schmidt
M
M
Lu
Y
Y
Mendelsohn
J
J
Fan
Z
Z
D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000972:Antineoplastic Agents, Phytogenic / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics / Q000502:physiology*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000502:physiology*; D020319:Oligodeoxyribonucleotides, Antisense / Q000235:genetics; D017239:Paclitaxel / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D009363:Neoplasm Proteins; D020319:Oligodeoxyribonucleotides, Antisense; D011993:Recombinant Fusion Proteins; D004815:Epidermal Growth Factor; D016203:CDC2 Protein Kinase; D017239:Paclitaxel