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

Molecular cancer therapeutics (2009-07-09)
Wen-Xing Ding, Hong-Min Ni, Wentao Gao, Xiaoyun Chen, Jeong Han Kang, Donna B Stolz, Jinsong Liu, Xiao-Ming Yin
ABSTRACT

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.

MATERIALS
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Product Description

Sigma-Aldrich
Medium 199, Modified, with Earle′s salts, without L-glutamine, sodium bicarbonate, and phenol red, powder, suitable for cell culture
Sigma-Aldrich
Medium 199, With Earle′s salts and sodium bicarbonate, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Medium 199, 10 ×, With Hanks′ salts, without L-glutamine and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Medium 199, With Earle′s salts, L-glutamine and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Medium 199, HEPES Modification, with Earle′s salts, L-glutamine and 25 mM HEPES, without sodium bicarbonate, powder, suitable for cell culture
Sigma-Aldrich
Medium 199, With Hanks′ salts and L-glutamine, without sodium bicarbonate, powder, suitable for cell culture
Sigma-Aldrich
Medium 199, With Hanks′ salts and sodium bicarbonate, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Medium 199, HEPES Modification, with Earle′s salts, 25 mM HEPES and sodium bicarbonate, without L-glutamine, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Medium 199, 10 ×, With Earle′s salts, without L-glutamine and sodium bicarbonate, liquid, sterile-filtered, suitable for cell culture
Sigma-Aldrich
Medium 199, With Earle′s salts and L-glutamine, without sodium bicarbonate, powder, suitable for cell culture