Document Detail


OSU-03012 suppresses GRP78/BiP expression that causes PERK-dependent increases in tumor cell killing.
MedLine Citation:
PMID:  22354011     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
We have further defined mechanism(s) by which the drug OSU-03012 (OSU) kills tumor cells. OSU lethality was suppressed by knock down of PERK and enhanced by knock down of ATF6 and IRE1α. OSU treatment suppressed expression of the chaperone, BiP/GRP78, and did so through reduced stability of the protein. Knock down of BiP/GRP78 further enhanced OSU lethality. Overexpression of BiP/GRP78 abolished OSU toxicity. Pre-treatment of cells with OSU enhanced radiosensitivity to a greater extent than concomitant or sequential drug treatment with radiation exposure. Expression of a mutant active p110 PI3K, or mutant active forms of the EGFR in GBM cells did not differentially suppress OSU killing. In contrast loss of PTEN function reduced OSU lethality, without altering AKT, p70 S6K or mTOR activity, or the drug's ability to radiosensitize GBM cells. Knock down of PTEN protected cells from OSU and radiation treatment whereas re-expression of PTEN facilitated drug lethality and radiosensitization. In a dose-dependent fashion OSU prolonged the survival of mice carrying GBM tumors and interacted with radiotherapy to further prolong survival. Collectively, our data show that reduced BiP/GRP78 levels play a key role in OSU-3012 toxicity in GBM cells, and that this drug has in vivo activity against an invasive primary human GBM isolate.
Authors:
Laurence Booth; Sophie C Cazanave; Hossein A Hamed; Adly Yacoub; Besim Ogretmen; Ching-Shih Chen; Steven Grant; Paul Dent
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Cancer biology & therapy     Volume:  13     ISSN:  1555-8576     ISO Abbreviation:  Cancer Biol. Ther.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-22     Completed Date:  2012-09-18     Revised Date:  2013-12-08    
Medline Journal Info:
Nlm Unique ID:  101137842     Medline TA:  Cancer Biol Ther     Country:  United States    
Other Details:
Languages:  eng     Pagination:  224-36     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Death / drug effects
Cell Line, Tumor
Cell Survival / drug effects
Colonic Neoplasms / drug therapy,  genetics,  metabolism,  pathology
Gene Knockdown Techniques
Glioblastoma / drug therapy,  genetics,  metabolism,  pathology
Heat-Shock Proteins / antagonists & inhibitors*,  biosynthesis*,  metabolism
Humans
Mice
PTEN Phosphohydrolase / metabolism
Pyrazoles / pharmacology*
Sulfonamides / pharmacology*
Transfection
eIF-2 Kinase / metabolism*
Grant Support
ID/Acronym/Agency:
P01-CA104177/CA/NCI NIH HHS; R01 CA141703/CA/NCI NIH HHS; R01 CA150214/CA/NCI NIH HHS; R01 DK052825/DK/NIDDK NIH HHS; R01-CA141188/CA/NCI NIH HHS; R01-CA63753/CA/NCI NIH HHS; R01-CA77141/CA/NCI NIH HHS; R01-DK52825/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Heat-Shock Proteins; 0/OSU 03012; 0/Pyrazoles; 0/Sulfonamides; 0/molecular chaperone GRP78; EC 2.7.10.-/PERK kinase; EC 2.7.11.1/eIF-2 Kinase; EC 3.1.3.48/PTEN protein, human; EC 3.1.3.48/Pten protein, mouse; EC 3.1.3.67/PTEN Phosphohydrolase
Comments/Corrections

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