Phosphorylation and stabilization of topoisomerase IIα protein by p38γ mitogen-activated protein kinase sensitize breast cancer cells to its poisons

Xiaomei Qi, Songwang Hou, Adrienne Lepp, Rongshan Li, Zainab Basir, Zhenkun Lou, Guan Chen

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Cancer drugs suppress tumor cell growth by inhibiting specific cellular targets. However, most drugs also activate several cellular nonspecific stress pathways, and the implications of these off-target effects are mostly unknown. Here, we report that p38γ, but not p38α, MAPK is specifically activated by treatment of breast cancer cells with topoisomerase II (Topo II) drugs, whereas paclitaxel (Taxol) does not have this effect. The activated p38γ in turn phosphorylates and stabilizes Topo IIαprotein, and this enhances the growth inhibition by Topo II drugs. Moreover, p38γ activity was shown to be necessary and sufficient for Topo IIα expression, the drug-p38γ-Topo IIα axis is only detected in intrinsically sensitive but not resistant cells, and p38γ is co-overexpressed with Topo IIα protein in primary breast cancers. These results reveal a new paradigm in which p38γ actively regulates the drug-Topo IIα signal transduction, and this may be exploited to increase the therapeutic activity of Topo II drugs.

Original languageEnglish (US)
Pages (from-to)35883-35890
Number of pages8
JournalJournal of Biological Chemistry
Volume286
Issue number41
DOIs
StatePublished - Oct 14 2011

Fingerprint

Type II DNA Topoisomerase
Phosphorylation
Poisons
p38 Mitogen-Activated Protein Kinases
Stabilization
Cells
Breast Neoplasms
Pharmaceutical Preparations
Proteins
Paclitaxel
Signal transduction
Cell growth
Growth
Tumors
Signal Transduction
Neoplasms

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Phosphorylation and stabilization of topoisomerase IIα protein by p38γ mitogen-activated protein kinase sensitize breast cancer cells to its poisons. / Qi, Xiaomei; Hou, Songwang; Lepp, Adrienne; Li, Rongshan; Basir, Zainab; Lou, Zhenkun; Chen, Guan.

In: Journal of Biological Chemistry, Vol. 286, No. 41, 14.10.2011, p. 35883-35890.

Research output: Contribution to journalArticle

Qi, Xiaomei ; Hou, Songwang ; Lepp, Adrienne ; Li, Rongshan ; Basir, Zainab ; Lou, Zhenkun ; Chen, Guan. / Phosphorylation and stabilization of topoisomerase IIα protein by p38γ mitogen-activated protein kinase sensitize breast cancer cells to its poisons. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 41. pp. 35883-35890.
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