Cell Growth & Differentiation, Vol 9, Issue 8 687-697, Copyright © 1998 by American Association of Cancer Research

ARTICLES

Taxanes propagate apoptosis via two cell populations with distinctive cytological and molecular traits

PJ Moos and FA Fitzpatrick
Department of Oncological Science, Huntsman Cancer Institute, University of Utah, Salt Lake City 84112, USA.

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.

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