Taxanes propagate apoptosis via two cell populations with distinctive cytological and molecular traits.
Taxol and Taxotere propagate apoptosis in Jurkat T cells via molecular signals that coincide with the appearance of two distinct cell populations. Cell cycle arrest in G2-M phase and activation of cell cycle-dependent kinases begin within 2 h and extend to most cells by 16 h. Phosphorylation of Bcl-2 also begins within 2 h and intensifies from 2-16 h. Cell cycle arrest, activation of mitotic kinases, and phosphorylation of Bcl-2 coincided with the appearance of a population of metastable cells that accumulate YO-PRO-1 dye, are resistant to the caspase inhibitor carbobenzoxy-L-aspartyl-alpha-[(2,6-dichlorobenzoyl)oxy]methane, and have intact genomic DNA. Phosphorylation and deactivation of kinases that relay survival/mitogenesis signals in T cells begin after 8 h and are prominent by 12-16 h. Deactivated kinases include c-Raf-1, p44 extracellular receptor kinase, and the tyrosine kinases c-Lck and ZAP-70. Activation of Mr 40,000 and Mr 52,000 kinases is also prominent by 12-16 h. The modulation of all these kinases coincided with the activation of caspase-3 at 12 h and the appearance of a population of apoptotic cells that accumulate YO-PRO-1, are susceptible to the caspase inhibitor carbobenzoxy-L-aspartyl-alpha-[(2,6-dichloro-benzoyl)oxy]methane, and contain fragmented genomic DNA. This distinctive apoptosis signaling pathway may help account for the superior cytotoxic efficacy of taxanes in certain types of cancer.
Department of Oncological Science, Huntsman Cancer Institute, University of Utah, Salt Lake City 84112, USA.
P J
PJ
Moos
F A
FA
Fitzpatrick
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle; D019926:Cyclin B / Q000378:metabolism; D056744:Cyclin B1; D053938:DNA Fragmentation; D000077143:Docetaxel; D004789:Enzyme Activation; D005434:Flow Cytometry; D006801:Humans; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000031:analogs & derivatives* / Q000494:pharmacology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism; D043823:Taxoids; D051746:ZAP-70 Protein-Tyrosine Kinase
D000972:Antineoplastic Agents, Phytogenic; C534699:CCNB1 protein, human; D019926:Cyclin B; D056744:Cyclin B1; D019253:Proto-Oncogene Proteins c-bcl-2; D043823:Taxoids; D000077143:Docetaxel; D011505:Protein-Tyrosine Kinases; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D051746:ZAP-70 Protein-Tyrosine Kinase; C497261:ZAP70 protein, human; D019908:Proto-Oncogene Proteins c-raf; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D016203:CDC2 Protein Kinase; D019950:Mitogen-Activated Protein Kinase 1; C505407:CASP3 protein, human; D053148:Caspase 3; D020169:Caspases; D017239:Paclitaxel; D015739:Nocodazole