Document Detail


AKT inhibition mitigates GRP78 (glucose-regulated protein) expression and contribution to chemoresistance in endometrial cancers.
MedLine Citation:
PMID:  23280503     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Overexpression of the unfolded protein response master regulator GRP78 is associated with poor prognosis and therapeutic resistance in numerous human cancers, yet its role in endometrial cancers (EC) is undefined. To better understand the contribution of GRP78 to EC, we examined its expression levels in EC patient samples and EC cell lines. We demonstrate that GRP78 overexpression occurs more frequently in EC tissues compared with that found in normal endometrium, and that GRP78 expression occurs in most EC cell lines examined. Functional analysis demonstrated that GRP78 is inducible by cisplatin in EC cells, and siRNA knockdown of GRP78 augments chemotherapy-mediated cell death. Examination of AKT and GRP78 expression demonstrated that inhibition of AKT activity by MK2206 blocks GRP78 expression in EC cells. SiRNA studies also revealed that knockdown of GRP78 reduces but does not abrogate AKT activity, demonstrating that GRP78 is required for optimal AKT activity. In the presence of MK2206, siRNA knockdown of GRP78 does not augment AKT mediated survival in response to cisplatin treatment, suggesting that GRP78's antiapoptosis functions are part of the AKT survival pathway. Targeted therapies that reduce GRP78 expression or activity in cancers may serve to increase the effectiveness of current therapies for EC patients.
Authors:
Michael J Gray; Paulette Mhawech-Fauceglia; Eunjeong Yoo; Wangrong Yang; Eijean Wu; Amy S Lee; Yvonne G Lin
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-02-08
Journal Detail:
Title:  International journal of cancer. Journal international du cancer     Volume:  133     ISSN:  1097-0215     ISO Abbreviation:  Int. J. Cancer     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-04-22     Completed Date:  2013-06-11     Revised Date:  2014-07-02    
Medline Journal Info:
Nlm Unique ID:  0042124     Medline TA:  Int J Cancer     Country:  United States    
Other Details:
Languages:  eng     Pagination:  21-30     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 UICC.
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Antineoplastic Agents / pharmacology*,  therapeutic use
Apoptosis / drug effects
Cell Line, Tumor
Cisplatin / pharmacology*,  therapeutic use
Drug Resistance, Neoplasm* / drug effects
Endometrial Neoplasms / drug therapy*,  metabolism*
Female
Gene Expression Regulation, Neoplastic / drug effects
Gene Knockdown Techniques
Heat-Shock Proteins / drug effects,  genetics,  metabolism*
Heterocyclic Compounds, 3-Ring / pharmacology*,  therapeutic use
Humans
Middle Aged
Protein Kinase Inhibitors / pharmacology*,  therapeutic use
Proto-Oncogene Proteins c-akt / antagonists & inhibitors*
RNA, Small Interfering
Grant Support
ID/Acronym/Agency:
CA027607/CA/NCI NIH HHS; P30 CA014089/CA/NCI NIH HHS; P30CA014089/CA/NCI NIH HHS; R01 CA027607/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Heat-Shock Proteins; 0/Heterocyclic Compounds, 3-Ring; 0/MK 2206; 0/Protein Kinase Inhibitors; 0/RNA, Small Interfering; 0/molecular chaperone GRP78; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; Q20Q21Q62J/Cisplatin
Comments/Corrections

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


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