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Monosaccharide digitoxin derivative sensitize human non-small cell lung cancer cells to anoikis through Mcl-1 proteasomal degradation.

Authors
Pongrakhananon-V; Stueckle-TA; Wang-H-YL; O'Doherty-GA; Dinu-CZ; Chanvorachote-P; Rojanasakul-Y
Source
Biochem Pharmacol 2014 Mar; 88(1):23-35
NIOSHTIC No.
20043481
Abstract
Advanced stage cancers acquire anoikis resistance which provides metastatic potential to invade and form tumors at distant sites. Suppression of anoikis resistance by novel molecular therapies would greatly benefit treatment strategies for metastatic cancers. Recently, digitoxin and several of its novel synthetic derivatives, such as -L-rhamnose monosaccharide derivative (D6-MA), have been synthesized and studied for their profound anticancer activity in various cancer cell lines. In this study, we investigated the anoikis sensitizing effect of D6-MA compared with digitoxin to identify their anti-metastatic mechanism of action. D6-MA sensitized NSCLC H460 cells to detachment-induced apoptosis with significantly greater cytotoxicity (IC50 = 11.9 nM) than digitoxin (IC50 = 90.7 nM) by activating caspase-9. Screening of the Bcl-2 protein family revealed that degradation of anti-apoptotic Mcl-1 protein is a favorable target. Mcl-1 over-expression and knockdown studies in D6-MA and digitoxin exposed cells resulted in rescue and enhancement, respectively, indicating a facilitative role for decreased Mcl-1 expression in NSCLC anoikis. Transfection with mutant Mcl-1S159 attenuated detachment-induced cell death and correlated with a remaining of Mcl-1 level. Furthermore, D6-MA suppressed Mcl-1 expression via ubiquitin proteasomal degradation that is dependent on activation of glycogen synthase kinase (GSK)-3 signaling. In addition, D6-MA also targeted Mcl-1 degradation causing an increased anoikis in A549 lung cancer cells. Anoikis sensitizing effect on normal small airway epithelial cells was not observed indicating the specificity of D6-MA and digitoxin for NSCLC. These results identify a novel cardiac glycoside (CG) sensitizing anoikis mechanism and provide a promising anti-metastatic target for lung cancer therapy.
Keywords
Cancer; Tumors; Cell-function; Cell-biology; Cellular-reactions; Cellular-structures; Cytotoxicity; Proteins; Mutation; Lung-cells; Author Keywords: monosaccharide digitoxin derivative; anoikis; Mcl-1; glycogen synthase kinase -3; metastasis; NSCLC
Contact
Prof. Yon Rojanasakul, Basic Pharmaceutical Sciences, West Virginia University, Morgantown, WV 26505
CODEN
BCPCA6
Publication Date
20140301
Document Type
Journal Article
Email Address
yrojan@hsc.wdu.edu
Fiscal Year
2014
NTIS Accession No.
NTIS Price
Identifying No.
M122013
Issue of Publication
1
ISSN
0006-2952
NIOSH Division
HELD
Priority Area
Manufacturing
Source Name
Biochemical Pharmacology
State
WV; MA
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