title: The possible correlation between activation of NF-kappaB/IkappaB pathway and the susceptibility of tumor cells to paclitaxel-induced apoptosis.
abstract: Paclitaxel (Taxol) is a naturally occurring antimitotic agent that has been shown to induce apoptosis in both leukemic and solid tumor cells, but many tumor cells exhibit a high resistance to paclitaxel. The mechanism of different susceptibility among tumor cells to paclitaxel-induced apoptotic cell death is not entirely clear. In this study, we identified and characterized two solid tumor cell lines, human breast tumor MCF7 cells and rat prostate tumor R3227 cells, which were resistant to paclitaxel-induced apoptosis. The results indicated that these tumor cells were highly resistant to paclitaxel-induced nucleosomal DNA fragmentation, but still sensitive to paclitaxel-induced microtubule bundling and cell cycle arrest at G2-M. This selective resistance of MCF7 and R3227 to paclitaxel suggests that mitotic arrest and apoptotic cell death might be two separate events, and paclitaxel-induced mitotic arrest may not always be followed by apoptotic cell death. Further, through comparative studies and analyses of a number of genes whose expression or activation may be involved in the regulation of apoptotic cell death or drug resistance, we found that paclitaxel induced the degradation of IkappaBalpha protein, which in turn activated NF-kappaB in paclitaxel-sensitive tumor cells, but such a paclitaxel-induced activation of the NF-kappaB/IkappaBalpha cascade was not observed in either MCF7 or R3227 cells. These findings suggest that the activation of NF-kappaB/IkappaBalpha signaling pathway might play an important role in determining the susceptibility of tumor cells to paclitaxel-induced apoptosis.
authors.affiliation: Department of Pathology, Medical University of South Carolina, Charleston 29425, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.forename: Yong
authors.initials: Y
authors.lastname: Fang
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Dziadyk
authors.forename: James S
authors.initials: JS
authors.lastname: Norris
authors.forename: Weimin
authors.initials: W
authors.lastname: Fan
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000032:analysis; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D016195:G2 Phase / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase; D020672:I-kappa B Proteins / Q000378:metabolism*; D048728:MAP Kinase Kinase Kinase 1; D008938:Mitosis / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000493:pharmacokinetics / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000972:Antineoplastic Agents, Phytogenic; D020672:I-kappa B Proteins; D016328:NF-kappa B; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D017239:Paclitaxel