p38 Mitogen-activated protein kinase mediates cell death and p21-activated kinase mediates cell survival during chemotherapeutic drug-induced mitotic arrest

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...

Full description

Saved in:
Bibliographic Details
Published in:Molecular biology of the cell 2003-05, Vol.14 (5), p.2071-2087
Main Authors: Deacon, Karl, Mistry, Pratibha, Chernoff, Jonathan, Blank, Jonathan L, Patel, Rajnikant
Format: Article
Language:English
Subjects:
Antineoplastic Agents - pharmacology
Apoptosis - drug effects
bcl-2-Associated X Protein
Cell Survival - drug effects
Cytoplasm - metabolism
HeLa Cells
Humans
Mitochondria - metabolism
Mitogen-Activated Protein Kinases - drug effects
Mitosis - drug effects
Nocodazole - pharmacology
p21-Activated Kinases
p38 Mitogen-Activated Protein Kinases
Protein-Serine-Threonine Kinases - drug effects
Proto-Oncogene Proteins - metabolism
Proto-Oncogene Proteins c-bcl-2
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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.
ISSN:1059-1524
1939-4586
DOI:10.1091/mbc.E02-10-0653