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

Wen Xing Ding, Hong Min Ni, Wentao Gao, Xiaoyun Chen, Han Kang Jeong, Donna B. Stolz, Jinsong Liu, Xiao Ming Yin

Research output: Contribution to journalArticlepeer-review

84 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2036-2045
Number of pages10
JournalMolecular cancer therapeutics
Volume8
Issue number7
DOIs
StatePublished - Jul 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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