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 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.
Institute of Molecular and Cellular Biosciences, University of Tokyo, Bunkyo-ku, Tokyo 113-0032, Japan.
Yasunari
Y
Ogiso
Akihiro
A
Tomida
Takashi
T
Tsuruo
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D003546:Cysteine Endopeptidases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D005047:Etoposide / Q000494:pharmacology; D005947:Glucose / Q000172:deficiency; D019073:HT29 Cells / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D006801:Humans; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D019913:Nuclear Localization Signals / Q000235:genetics / Q000502:physiology*; D046988:Proteasome Endopeptidase Complex; D013312:Stress, Physiological / Q000378:metabolism*; D059005:Topoisomerase II Inhibitors; D014162:Transfection; D014750:Vincristine / Q000494:pharmacology
D000972:Antineoplastic Agents, Phytogenic; D009097:Multienzyme Complexes; D019913:Nuclear Localization Signals; D059005:Topoisomerase II Inhibitors; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D005947:Glucose