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.
authors: Department of Pharmacology, Toxicology, and Therapeutics, The University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors: Wen-Xing
authors: WX
authors: Ding
authors: Xi
authors: X
authors: Chen
authors: Xiao-Ming
authors: XM
authors: Yin
mesh_terms: D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D001343:Autophagy; D000071187:Autophagy-Related Protein 5; D000071186:Beclin-1; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009369:Neoplasms / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: C502778:ATG5 protein, human; D051017:Apoptosis Regulatory Proteins; D000071187:Autophagy-Related Protein 5; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D061988:Proteasome Inhibitors; D034741:RNA, Small Interfering; D046988:Proteasome Endopeptidase Complex