Phosphorylation and stabilization of topoisomerase IIα protein by p38γ mitogen-activated protein kinase sensitize breast cancer cells to its poisons. J Biol Chem 2011 Oct 14;286(41):35883-35890
Date
09/01/2011Pubmed ID
21878638Pubmed Central ID
PMC3195563DOI
10.1074/jbc.M111.229260Scopus ID
2-s2.0-80053896975 (requires institutional sign-in at Scopus site) 25 CitationsAbstract
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 IIα protein, 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.
Author List
Qi X, Hou S, Lepp A, Li R, Basir Z, Lou Z, Chen GAuthor
Guan Chen MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Antigens, NeoplasmAntineoplastic Agents, Phytogenic
Breast Neoplasms
DNA Topoisomerases, Type II
DNA-Binding Proteins
Female
Gene Expression Regulation, Enzymologic
Gene Expression Regulation, Neoplastic
Humans
Mitogen-Activated Protein Kinase 12
Paclitaxel
Signal Transduction
