Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy

The proteasome and the autophagy systems are two evolutionarily conserved mechanisms for degrading intracellular materials. They are functionally coupled and suppression of the proteasome promotes autophagy. Although suppression of the proteasome leads to cell death, suppression of autophagy can be...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2009-07, Vol.8 (7), p.2036-2045
Main Authors: Ding, Wen-Xing, Ni, Hong-Min, Gao, Wentao, Chen, Xiaoyun, Kang, Jeong Han, Stolz, Donna B, Liu, Jinsong, Yin, Xiao-Ming
Format: Article
Language:English
Subjects:
Animals
Antimalarials - pharmacology
Apoptosis
autophagy
Autophagy - drug effects
Blotting, Western
Boronic Acids - pharmacology
Bortezomib
cancer therapy
Cell Line, Tumor
Cell Proliferation
Cell Transformation, Neoplastic
Chloroquine - pharmacology
Colonic Neoplasms - drug therapy
Colonic Neoplasms - metabolism
Colonic Neoplasms - pathology
Drug Therapy, Combination
Female
Humans
macroautophagy
Mice
Mice, Inbred BALB C
Mice, Nude
Protease Inhibitors - pharmacology
Proteasome Inhibitors
Pyrazines - pharmacology
Xenograft Model Antitumor Assays
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Summary:The proteasome and the autophagy systems are two evolutionarily conserved mechanisms for degrading intracellular materials. They are functionally coupled and suppression of the proteasome promotes autophagy. Although suppression of the proteasome leads to cell death, suppression of autophagy can be either prodeath or prosurvival. To understand the underlining mechanism of this dichotomy and its potential clinical implications, we treated various transformed and nontransformed human cells with proteasome inhibitors. We found that whether autophagy served a prosurvival role in this scenario was contingent on the cellular oncogenic status. Thus, autophagy suppression enhanced apoptosis induced by proteasome inhibitors in transformed cells, but not in nontransformed cells. Oncogenic transformation enhanced the ability of cells to initiate autophagy in response to stress, reflecting a stronger dependence of transformed cells on autophagy for survival. Indeed, a combined use of bortezomib, the only Food and Drug Administration–approved proteasome inhibitor for clinical use, and chloroquine, which inhibits autophagy by disturbing lysosomal functions, suppressed tumor growth more significantly than either agent alone in a xenograft model. These findings indicate that suppression of both intracellular degradation systems could constitute a novel strategy for enhanced cancer control in a tumor-specific way. [Mol Cancer Ther 2009;8(7):2036–45]
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-08-1169