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 journalArticle

80 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Autophagy
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Neoplasms
Chloroquine
United States Food and Drug Administration
Heterografts
Cell Death
Apoptosis
Survival
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy. / Ding, Wen Xing; Ni, Hong Min; Gao, Wentao; Chen, Xiaoyun; Jeong, Han Kang; Stolz, Donna B.; Liu, Jinsong; Yin, Xiao-Ming.

In: Molecular Cancer Therapeutics, Vol. 8, No. 7, 01.07.2009, p. 2036-2045.

Research output: Contribution to journalArticle

Ding, Wen Xing ; Ni, Hong Min ; Gao, Wentao ; Chen, Xiaoyun ; Jeong, Han Kang ; Stolz, Donna B. ; Liu, Jinsong ; Yin, Xiao-Ming. / Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy. In: Molecular Cancer Therapeutics. 2009 ; Vol. 8, No. 7. pp. 2036-2045.
@article{59494e03ef6246738379c85e17212659,
title = "Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy",
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.",
author = "Ding, {Wen Xing} and Ni, {Hong Min} and Wentao Gao and Xiaoyun Chen and Jeong, {Han Kang} and Stolz, {Donna B.} and Jinsong Liu and Xiao-Ming Yin",
year = "2009",
month = "7",
day = "1",
doi = "10.1158/1535-7163.MCT-08-1169",
language = "English (US)",
volume = "8",
pages = "2036--2045",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - Oncogenic transformation confers a selective susceptibility to the combined suppression of the proteasome and autophagy

AU - Ding, Wen Xing

AU - Ni, Hong Min

AU - Gao, Wentao

AU - Chen, Xiaoyun

AU - Jeong, Han Kang

AU - Stolz, Donna B.

AU - Liu, Jinsong

AU - Yin, Xiao-Ming

PY - 2009/7/1

Y1 - 2009/7/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=67651155954&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67651155954&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-08-1169

DO - 10.1158/1535-7163.MCT-08-1169

M3 - Article

C2 - 19584239

AN - SCOPUS:67651155954

VL - 8

SP - 2036

EP - 2045

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 7

ER -