Tumor cells can evade dependence on autophagy through adaptation

Wen Xing Ding, Xi Chen, Xiao-Ming Yin

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

The autophagy-lysosome and the proteasome constitute the two major intracellular degradation systems. Suppression of the proteasome promotes autophagy for compensation and simultaneous inhibition of autophagy can selectively increase apoptosis in transformed cells, but not in untransformed or normal cells. Transformed cells are thus more dependent on autophagy for survival. However, it is unclear whether long-term autophagy inhibition/insufficiency would affect such dependency. To address this question, we transformed wild-type and autophagy-deficient cells lacking a key autophagy-related gene Atg5 with activated Ras. We found that such transformation did not make the autophagy-deficient tumor cells more susceptible to proteasome inhibitors than the wild type tumor cells, although the transformed cells were in general more sensitive to proteasome inhibition. We then compared the effect of acute versus constitutive knock-down of a key autophagy initiating molecule, Beclin 1, in an already transformed cancer cell line. In a wild-type U251 glioblastoma cell line (autophagy intact), increased sensitivity to proteasome inhibition was induced immediately after the knock-down of Beclin 1 expression with a specific siRNA (acute autophagy deficiency). On the other hand, when the tumor cell line was selected over a long period to achieve constitutive knock-down of Beclin 1, its sensitivity to proteasome inhibitors was no higher than that of the wild-type tumor cells. These results suggest that long-term autophagy deficiency either before or after oncogenic transformation can render the tumor cell survival independent of the autophagic activity, and the response to chemotherapy is no longer affected by the manipulation of the autophagy status.

Original languageEnglish
Pages (from-to)684-688
Number of pages5
JournalBiochemical and Biophysical Research Communications
Volume425
Issue number3
DOIs
StatePublished - Aug 31 2012

Fingerprint

Autophagy
Tumors
Cells
Proteasome Endopeptidase Complex
Neoplasms
Proteasome Inhibitors
Chemotherapy
Small Interfering RNA
Genes
Apoptosis
Transformed Cell Line
Degradation
Molecules
Glioblastoma
Lysosomes
Tumor Cell Line
Cell Survival

Keywords

  • Anticancer therapy
  • Autophagy
  • Proteasome inhibitors

ASJC Scopus subject areas

  • Biochemistry
  • Biophysics
  • Cell Biology
  • Molecular Biology

Cite this

Tumor cells can evade dependence on autophagy through adaptation. / Ding, Wen Xing; Chen, Xi; Yin, Xiao-Ming.

In: Biochemical and Biophysical Research Communications, Vol. 425, No. 3, 31.08.2012, p. 684-688.

Research output: Contribution to journalArticle

@article{1593105966c74e7f88c247a377a396d0,
title = "Tumor cells can evade dependence on autophagy through adaptation",
abstract = "The autophagy-lysosome and the proteasome constitute the two major intracellular degradation systems. Suppression of the proteasome promotes autophagy for compensation and simultaneous inhibition of autophagy can selectively increase apoptosis in transformed cells, but not in untransformed or normal cells. Transformed cells are thus more dependent on autophagy for survival. However, it is unclear whether long-term autophagy inhibition/insufficiency would affect such dependency. To address this question, we transformed wild-type and autophagy-deficient cells lacking a key autophagy-related gene Atg5 with activated Ras. We found that such transformation did not make the autophagy-deficient tumor cells more susceptible to proteasome inhibitors than the wild type tumor cells, although the transformed cells were in general more sensitive to proteasome inhibition. We then compared the effect of acute versus constitutive knock-down of a key autophagy initiating molecule, Beclin 1, in an already transformed cancer cell line. In a wild-type U251 glioblastoma cell line (autophagy intact), increased sensitivity to proteasome inhibition was induced immediately after the knock-down of Beclin 1 expression with a specific siRNA (acute autophagy deficiency). On the other hand, when the tumor cell line was selected over a long period to achieve constitutive knock-down of Beclin 1, its sensitivity to proteasome inhibitors was no higher than that of the wild-type tumor cells. These results suggest that long-term autophagy deficiency either before or after oncogenic transformation can render the tumor cell survival independent of the autophagic activity, and the response to chemotherapy is no longer affected by the manipulation of the autophagy status.",
keywords = "Anticancer therapy, Autophagy, Proteasome inhibitors",
author = "Ding, {Wen Xing} and Xi Chen and Xiao-Ming Yin",
year = "2012",
month = "8",
day = "31",
doi = "10.1016/j.bbrc.2012.07.090",
language = "English",
volume = "425",
pages = "684--688",
journal = "Biochemical and Biophysical Research Communications",
issn = "0006-291X",
publisher = "Academic Press Inc.",
number = "3",

}

TY - JOUR

T1 - Tumor cells can evade dependence on autophagy through adaptation

AU - Ding, Wen Xing

AU - Chen, Xi

AU - Yin, Xiao-Ming

PY - 2012/8/31

Y1 - 2012/8/31

N2 - The autophagy-lysosome and the proteasome constitute the two major intracellular degradation systems. Suppression of the proteasome promotes autophagy for compensation and simultaneous inhibition of autophagy can selectively increase apoptosis in transformed cells, but not in untransformed or normal cells. Transformed cells are thus more dependent on autophagy for survival. However, it is unclear whether long-term autophagy inhibition/insufficiency would affect such dependency. To address this question, we transformed wild-type and autophagy-deficient cells lacking a key autophagy-related gene Atg5 with activated Ras. We found that such transformation did not make the autophagy-deficient tumor cells more susceptible to proteasome inhibitors than the wild type tumor cells, although the transformed cells were in general more sensitive to proteasome inhibition. We then compared the effect of acute versus constitutive knock-down of a key autophagy initiating molecule, Beclin 1, in an already transformed cancer cell line. In a wild-type U251 glioblastoma cell line (autophagy intact), increased sensitivity to proteasome inhibition was induced immediately after the knock-down of Beclin 1 expression with a specific siRNA (acute autophagy deficiency). On the other hand, when the tumor cell line was selected over a long period to achieve constitutive knock-down of Beclin 1, its sensitivity to proteasome inhibitors was no higher than that of the wild-type tumor cells. These results suggest that long-term autophagy deficiency either before or after oncogenic transformation can render the tumor cell survival independent of the autophagic activity, and the response to chemotherapy is no longer affected by the manipulation of the autophagy status.

AB - The autophagy-lysosome and the proteasome constitute the two major intracellular degradation systems. Suppression of the proteasome promotes autophagy for compensation and simultaneous inhibition of autophagy can selectively increase apoptosis in transformed cells, but not in untransformed or normal cells. Transformed cells are thus more dependent on autophagy for survival. However, it is unclear whether long-term autophagy inhibition/insufficiency would affect such dependency. To address this question, we transformed wild-type and autophagy-deficient cells lacking a key autophagy-related gene Atg5 with activated Ras. We found that such transformation did not make the autophagy-deficient tumor cells more susceptible to proteasome inhibitors than the wild type tumor cells, although the transformed cells were in general more sensitive to proteasome inhibition. We then compared the effect of acute versus constitutive knock-down of a key autophagy initiating molecule, Beclin 1, in an already transformed cancer cell line. In a wild-type U251 glioblastoma cell line (autophagy intact), increased sensitivity to proteasome inhibition was induced immediately after the knock-down of Beclin 1 expression with a specific siRNA (acute autophagy deficiency). On the other hand, when the tumor cell line was selected over a long period to achieve constitutive knock-down of Beclin 1, its sensitivity to proteasome inhibitors was no higher than that of the wild-type tumor cells. These results suggest that long-term autophagy deficiency either before or after oncogenic transformation can render the tumor cell survival independent of the autophagic activity, and the response to chemotherapy is no longer affected by the manipulation of the autophagy status.

KW - Anticancer therapy

KW - Autophagy

KW - Proteasome inhibitors

UR - http://www.scopus.com/inward/record.url?scp=84865561104&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84865561104&partnerID=8YFLogxK

U2 - 10.1016/j.bbrc.2012.07.090

DO - 10.1016/j.bbrc.2012.07.090

M3 - Article

C2 - 22842577

AN - SCOPUS:84865561104

VL - 425

SP - 684

EP - 688

JO - Biochemical and Biophysical Research Communications

JF - Biochemical and Biophysical Research Communications

SN - 0006-291X

IS - 3

ER -