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Vol. 14, Issue 5, 2071-2087, May 2003

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p38 Mitogen-Activated Protein Kinase Mediates Cell Death and p21-Activated Kinase Mediates Cell Survival during Chemotherapeutic Drug-induced Mitotic Arrest

Karl Deacon ^* , Pratibha Mistry , Jonathan Chernoff , Jonathan L. Blank ^*, and Rajnikant Patel  ^||

Departments of ^*Cell Physiology and Pharmacology, and Biochemistry, University of Leicester, Leicester LE1 7RH, United Kingdom; and The Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111

Submitted October 14, 2002; Revised November 22, 2002; Accepted December 27, 2002
Monitoring Editor: Marc Mumby

Activation of the mitotic checkpoint by chemotherapeutic drugs such as taxol causes mammalian cells to arrest in mitosis and then undergo apoptosis. However, the biochemical basis of chemotherapeutic drug-induced cell death is unclear. Herein, we provide new evidence that both cell survival and cell death-signaling pathways are concomitantly activated during mitotic arrest by microtubule-interfering drugs. Treatment of HeLa cells with chemotherapeutic drugs activated both p38 mitogen-activated protein kinase (MAPK) and p21-activated kinase (PAK). p38 MAPK was necessary for chemotherapeutic drug-induced cell death because the p38 MAPK inhibitors SB203580 or SB202190 suppressed cell death. Dominant-active MKK6, a direct activator of p38 MAPK, also induced cell death by stimulating translocation of Bax from the cytosol to the mitochondria in a p38 MAPK-dependent manner. Dominant active PAK suppressed this MKK6-induced cell death. PAK seems to mediate cell survival by phosphorylating Bad, and inhibition of PAK in mitotically arrested cells reduced Bad phosphorylation and increased apoptosis. Our results suggest that therapeutic strategies that suppress PAK-mediated survival signals may improve the efficacy of current cancer chemotherapies by enhancing p38 MAPK-mediated cell death.

Present address: AstraZeneca R&D Charnwood, Bakewell Road,Loughborough, Leicester, LE11 5RH, United Kingdom.

^|| Corresponding author. E-mail address: rp31{at}le.ac.uk.

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