Document Detail


Identification of unique sensitizing targets for anti-inflammatory CDDO-Me in metastatic melanoma by a large-scale synthetic lethal RNAi screening.
MedLine Citation:
PMID:  23020131     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
CDDO-Me has been shown to exert potent anti-inflammatory activity for chronic kidney disease and antitumor activity for several tumors, including melanoma, in early clinical trials. To improve CDDO-Me response in melanoma, we utilized a large-scale synthetic lethal RNAi screen targeting 6000 human druggable genes to identify targets that would sensitize melanoma cells to CDDO-Me. Based on screening results, five unique genes (GNPAT, SUMO1, SPINT2, FLI1, and SSX1) significantly potentiated the growth inhibitory effects of CDDO-Me and induced apoptosis in A375, a BRAF mutated melanoma line (P < 0.001). These five genes were then individually validated as targets to potentiate CDDO-Me activity, and related downstream signaling pathways of these genes were analyzed. In addition, the levels of phosphorylated Erk1/2, Akt, GSK-2, and PRAS40 were dramatically decreased by downregulating each of these five genes separately, suggesting a set of common mediators. Our findings indicate that GNPAT, SUMO1, SPINT2, FLI1, and SSX1 play critical roles in synergy with inflammation pathways in modulating melanoma cell survival and could serve as sensitizing targets to enhance CDDO-Me efficacy in melanoma growth control.
Authors:
Yong Qin; Wuguo Deng; Suhendan Ekmekcioglu; Elizabeth A Grimm
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-06
Journal Detail:
Title:  Pigment cell & melanoma research     Volume:  26     ISSN:  1755-148X     ISO Abbreviation:  Pigment Cell Melanoma Res     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-20     Completed Date:  2013-06-13     Revised Date:  2014-02-16    
Medline Journal Info:
Nlm Unique ID:  101318927     Medline TA:  Pigment Cell Melanoma Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  97-112     Citation Subset:  IM    
Copyright Information:
© 2012 John Wiley & Sons A/S.
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MeSH Terms
Descriptor/Qualifier:
Anti-Inflammatory Agents / pharmacology*,  therapeutic use
Apoptosis / drug effects,  genetics
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Screening Assays, Antitumor
Gene Expression Regulation, Neoplastic / drug effects
Gene Knockdown Techniques
Genes, Neoplasm / genetics
High-Throughput Screening Assays*
Humans
Melanoma / drug therapy*,  genetics,  pathology
Neoplasm Metastasis
Oleanolic Acid / analogs & derivatives*,  pharmacology,  therapeutic use
RNA Interference / drug effects*
RNA, Small Interfering / metabolism
Reproducibility of Results
Signal Transduction / drug effects,  genetics
Skin Neoplasms / drug therapy*,  genetics,  pathology
Treatment Outcome
Grant Support
ID/Acronym/Agency:
CA16672/CA/NCI NIH HHS; P30 CA016672/CA/NCI NIH HHS; P50 CA093459/CA/NCI NIH HHS; P50 CA093459/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/RNA, Small Interfering; 0/methyl 2-cyano-3,12-dioxoolean-1,9-dien-28-oate; 6SMK8R7TGJ/Oleanolic Acid
Comments/Corrections

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