Nuclear localization of proteasomes participates in stress-inducible resistance of solid tumor cells to topoisomerase II-directed drugs

Physiological cell conditions of solid tumors, such as glucose starvation and hypoxia,induce cellular resistance to topoisomerase II-directed drugs. Here, we show that the induction of drug resistance is mediated by nuclear accumulation of proteasomes, large multicatalytic protease complexes. We fou...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 2002-09, Vol.62 (17), p.5008-5012
Main Authors: OGISO, Yasunari, TOMIDA, Akihiro, TSURUO, Takashi
Format: Article
Language:English
Subjects:
Antineoplastic agents
Antineoplastic Agents, Phytogenic - pharmacology
Biological and medical sciences
Cell Cycle - drug effects
Cell Division - drug effects
Cell Nucleus - metabolism
Chemotherapy
Cysteine Endopeptidases - genetics
Cysteine Endopeptidases - metabolism
Cysteine Endopeptidases - physiology
Doxorubicin - pharmacology
Drug Resistance, Multiple - physiology
Drug Resistance, Neoplasm
Etoposide - pharmacology
Glucose - deficiency
HT29 Cells - drug effects
HT29 Cells - metabolism
HT29 Cells - physiology
Humans
Medical sciences
Multienzyme Complexes - genetics
Multienzyme Complexes - metabolism
Multienzyme Complexes - physiology
Nuclear Localization Signals - genetics
Nuclear Localization Signals - physiology
Pharmacology. Drug treatments
Proteasome Endopeptidase Complex
Stress, Physiological - metabolism
Topoisomerase II Inhibitors
Transfection
Vincristine - pharmacology
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Summary:Physiological cell conditions of solid tumors, such as glucose starvation and hypoxia,induce cellular resistance to topoisomerase II-directed drugs. Here, we show that the induction of drug resistance is mediated by nuclear accumulation of proteasomes, large multicatalytic protease complexes. We found that the nuclear proteasome accumulation during glucose starvation was attenuated by stable expression of a mutant type of proteasome subunit, XAPC7, that lacked the nuclear localization signal (NLS). It is important that the expression of NLS-defective XAPC7 also diminished the induction of resistance to etoposide and doxorubicin, typical topoisomerase II-directed drugs. Under normal conditions, however, the NLS-defective XAPC7 had little effect on either nuclear proteasome distribution or etoposide sensitivity. Our findings demonstrate that stress-induced nuclear proteasome accumulation occurs through up-regulation of the NLS-dependent transport. Inhibition of the nuclear proteasome accumulation can be a novel approach to circumventing resistance to topoisomerase II-directed drugs.
ISSN:0008-5472
1538-7445