Cooperative function of Chk1 and p38 pathways in activating G2 arrest following exposure to temozolomide

Yuicih Hirose, Makoto Katayama, Mitchel S. Berger, Russell O. Pieper

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Object. The Chk1 and p38 mitogen-activated protein kinase (MAPK) pathways play key roles in the G2 arrest caused by exposing glioma cells to temozolomide (TMZ). Although inhibition of either pathway sensitizes glioma cells to TMZ-induced cytotoxicity, the relative contributions of these pathways to TMZ-induced G2 arrest and to TMZ resistance conferred by G 2 arrest have not been defined. Methods. The authors pharmacologically inhibited the Chk1 and/or p38 pathways in U87MG human glioma cells prior to and/or after exposure to TMZ; thereafter, effects on the TMZ-induced G2 arrest pathway and toxicity were monitored. The p38 inhibitor SB203580 or the Chk1 inhibitor UCN-01 or their combination blocked TMZ-mediated inactivation of cdc25C and cdc2, suggesting that p38 and Chk1 pathways work cooperatively and are both necessary to inactivate cdc25C and cdc2. Consistent with this idea, the inhibition of both Chk1 and p38 pathways did not lead to greater bypass of TMZ-induced G2 arrest or greater cytotoxicity than inhibition of either pathway alone. Inhibition of p38 did not alter TMZ-induced Chk1 activation/phosphorylation and vice versa, suggesting that p38 and Chk1 do not cooperatively bring about G2 arrest by reciprocal activation/phosphorylation. The two pathways, however, are not functionally identical; the Chk1 pathway was required for both the initiation and maintenance of TMZ-induced G2 arrest, whereas the p38 pathway played a role only in the initiation. Conclusions. The Chk1 and p38 pathways cooperate to bring about TMZ-induced G2 arrest, and the inhibition of either pathway alone is sufficient to sensitize U87MG glioma cells to TMZ-induced cytotoxicity.

Original languageEnglish
Pages (from-to)1060-1065
Number of pages6
JournalJournal of neurosurgery
Volume100
Issue number6
DOIs
Publication statusPublished - 06-2004

All Science Journal Classification (ASJC) codes

  • Surgery
  • Clinical Neurology

Fingerprint Dive into the research topics of 'Cooperative function of Chk1 and p38 pathways in activating G<sub>2</sub> arrest following exposure to temozolomide'. Together they form a unique fingerprint.

  • Cite this