Microtubule dysfunction induced by paclitaxel initiates apoptosis through both c-Jun N-terminal kinase (JNK)-dependent and -independent pathways in ovarian cancer cells

Tzu Hao Wang, Diana M. Popp, Hsin Shih Wang, Masao Saitoh, Jane G. Mural, Donald C. Henley, Hidenori Ichijo, Jay Wimalasena*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

203 Scopus citations

Abstract

The antineoplastic agent paclitaxel (Taxol(TM)), a microtubule stabilizing agent, is known to arrest cells at the G2/M phase of the cell cycle and induce apoptosis. We and others have recently demonstrated that paclitaxel also activates the c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) signal transduction pathway in various human cell types, however, no clear role has been established for JNK/SAPK in paclitaxel-induced apoptosis. To further examine the role of JNK/SAPK signaling cascades in apoptosis resulting from microtubular dysfunction induced by paclitaxel, we have coexpressed dominant negative (dn) mutants of signaling proteins of the JNK/SAPK pathway (Ras, ASK1, Rac, NKK, and JNK) in human ovarian cancer cells with a selectable marker to analyze the apoptotic characteristics of cells expressing dn vectors following exposure to paclitaxel. Expression of these dn signaling proteins had no effect on Bcl-2 phosphorylation, yet inhibited apoptotic changes induced by paclitaxel up to 16 h after treatment. Coexpression of these dn signaling proteins had no protective effect after 48 h of paclitaxel treatment. Our data indicate that: (i) activated JNK/SAPK acts upstream of membrane changes and caspase-3 activation in paclitaxel-initiated apoptotic pathways, independently of Cell cycle stage, (ii) activated JNK/SAPK is not responsible for paclitaxel- induced phosphorylation of Bcl-2, and (iii) apoptosis resulting from microtubule damage may comprise multiple mechanisms, including a JNK/SAPK- dependent early phase and a JNK/SAPK-independent late phase.

Original languageEnglish
Pages (from-to)8208-8216
Number of pages9
JournalJournal of Biological Chemistry
Volume274
Issue number12
DOIs
StatePublished - 19 03 1999
Externally publishedYes

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