Document Detail


p38γ mitogen-activated protein kinase contributes to oncogenic properties maintenance and resistance to poly (ADP-ribose)-polymerase-1 inhibition in breast cancer.
MedLine Citation:
PMID:  21532888     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
p38γ MAPK, one of the four members of p38 mitogen-activated protein kinases (MAPKs), has previously been shown to harbor oncogenic functions. However, the biologic function of p38γ MAPK in breast cancer has not been well defined. In this study, we have shown that p38γ MAPK is overexpressed in highly metastatic human and mouse breast cancer cell lines and p38γ MAPK expression is preferentially associated with basal-like and metastatic phenotypes of breast tumor samples. Ectopic expression of p38γ MAPK did not lead to an increase in oncogenic properties in vitro in most tested mammary epithelial cells. However, knockdown of p38γ MAPK expression resulted in a dramatic decrease in cell proliferation, colony formation, cell migration, invasion in vitro and significant retardation of tumorigenesis, and long-distance metastasis to the lungs in vivo. Moreover, knockdown of p38γ MAPK triggered the activation of AKT signaling. Inhibition of this feedback loop with various PI3K/AKT signaling inhibitors facilitated the effect of targeting p38γ MAPK. We further found that overexpression of p38γ MAPK did not promote cell resistance to chemotherapeutic agents doxorubicin and paclitaxel but significantly increased cell resistance to PJ-34, a DNA damage agent poly (ADP-ribose)-polymerase-1 (PARP) inhibitor in vitro and in vivo. Finally, we identified that p38γ MAPK overexpression led to marked cell cycle arrest in G(2)/M phase. Our study for the first time clearly demonstrates that p38γ MAPK is a promising target for the design of targeted therapies for basal-like breast cancer with metastatic characteristics and for overcoming potential resistance against the PARP inhibitor.
Authors:
Fanyan Meng; Haijun Zhang; Gang Liu; Bas Kreike; Wei Chen; Seema Sethi; Fred R Miller; Guojun Wu
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Neoplasia (New York, N.Y.)     Volume:  13     ISSN:  1476-5586     ISO Abbreviation:  Neoplasia     Publication Date:  2011 May 
Date Detail:
Created Date:  2011-05-02     Completed Date:  2011-10-31     Revised Date:  2013-06-30    
Medline Journal Info:
Nlm Unique ID:  100886622     Medline TA:  Neoplasia     Country:  Canada    
Other Details:
Languages:  eng     Pagination:  472-82     Citation Subset:  IM    
Affiliation:
The Breast Cancer Biology Program, Barbara Ann Karmanos Cancer Institute, Detroit, MI, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Breast Neoplasms / enzymology*,  pathology
Cell Cycle / genetics
Cell Line, Tumor
Cell Movement / genetics
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Doxorubicin / pharmacology
Humans
Mice
Mitogen-Activated Protein Kinase 12 / genetics,  metabolism*
Neoplasm Invasiveness / genetics
Neoplasm Metastasis
Paclitaxel / pharmacology
Phenanthrenes / metabolism,  pharmacology
Phosphatidylinositol 3-Kinase / metabolism
Poly(ADP-ribose) Polymerases / antagonists & inhibitors,  metabolism*
Proto-Oncogene Proteins c-akt / metabolism
Signal Transduction
Chemical
Reg. No./Substance:
0/N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; 0/Phenanthrenes; 23214-92-8/Doxorubicin; 33069-62-4/Paclitaxel; EC 2.4.2.30/PARP1 protein, human; EC 2.4.2.30/Poly(ADP-ribose) Polymerases; EC 2.7.1.-/Mitogen-Activated Protein Kinase 12; EC 2.7.1.137/Phosphatidylinositol 3-Kinase; EC 2.7.11.1/Proto-Oncogene Proteins c-akt
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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