Loading…
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...
Saved in:
Published in: | Molecular cancer therapeutics 2009-07, Vol.8 (7), p.2036-2045 |
---|---|
Main Authors: | , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
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 |