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

Molecular Cancer Therapeutics - Tập 8 Số 7 - Trang 2036-2045 - 2009
Wen‐Xing Ding1,2, Hong‐Min Ni1,2, Wentao Gao1,2, Xiaoyun Chen1,2, Jeong Han Kang1,2, Donna B. Stolz1,2, Jinsong Liu1,2, Xiao‐Ming Yin1,2
1Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas
2Departments of 1Pathology and 2Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and 3Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas

Tóm tắt

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. [Mol Cancer Ther 2009;8(7):2036–45]

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Thông tin
Thông tin xuất bản

Molecular Cancer Therapeutics

Tập 8 Số 7

2036-2045

Thông tin tác giả