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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.
Afiliación
  • Qi X; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
  • Hou S; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
  • Lepp A; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
  • Li R; Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
  • Basir Z; Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
  • Lou Z; Department of Oncology, Mayo Clinic and Foundation, Rochester, Minnesota 55905.
  • Chen G; Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226; Department of Research Services, Zablocki Veterans Affairs Medical Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226. Electronic address: gchen@mcw.edu.
J Biol Chem ; 286(41): 35883-35890, 2011 Oct 14.
Article en En | MEDLINE | ID: mdl-21878638
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Regulación Enzimológica de la Expresión Génica / Regulación Neoplásica de la Expresión Génica / Paclitaxel / ADN-Topoisomerasas de Tipo II / Proteína Quinasa 12 Activada por Mitógenos / Proteínas de Unión al ADN / Antígenos de Neoplasias / Antineoplásicos Fitogénicos Límite: Female / Humans Idioma: En Revista: J Biol Chem Año: 2011 Tipo del documento: Article Pais de publicación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Mama / Regulación Enzimológica de la Expresión Génica / Regulación Neoplásica de la Expresión Génica / Paclitaxel / ADN-Topoisomerasas de Tipo II / Proteína Quinasa 12 Activada por Mitógenos / Proteínas de Unión al ADN / Antígenos de Neoplasias / Antineoplásicos Fitogénicos Límite: Female / Humans Idioma: En Revista: J Biol Chem Año: 2011 Tipo del documento: Article Pais de publicación: Estados Unidos