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Regulation of the multidrug resistance transporter P‐glycoprotein in multicellular tumor spheroids by hypoxia‐inducible factor‐1 and reactive oxygen species
Author(s) -
Wartenberg Maria,
Ling Frederike C.,
Müschen Markus,
Klein Florian,
Acker Helmut,
Gassmann Max,
Petrat Kerstin,
Pütz Volker,
Hescheler Jürgen,
Sauer Heinrich
Publication year - 2003
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.02-0358fje
Subject(s) - aryl hydrocarbon receptor nuclear translocator , chemistry , hypoxia (environmental) , hypoxia inducible factors , p glycoprotein , radioresistance , aryl hydrocarbon receptor , microbiology and biotechnology , reactive oxygen species , tumor hypoxia , biology , cancer research , multiple drug resistance , cell culture , biochemistry , transcription factor , oxygen , medicine , gene , genetics , organic chemistry , radiation therapy , antibiotics
Hypoxia in tumors is generally associated with chemoresistance and radioresistance. However, the correlation between the heterodimeric hypoxia‐inducible factor‐1 (HIF‐1) and the multidrug resistance transporter P‐glycoprotein (P‐gp) has not been investigated. Herein, we demonstrate that with increasing size of DU‐145 prostate multicellular tumor spheroids the pericellular oxygen pressure and the generation of reactive oxygen species decreased, whereas the α‐subunit of HIF‐1 (HIF‐1α) and P‐gp were up‐regulated. Furthermore, P‐gp was up‐regulated under experimental physiological hypoxia and chemical hypoxia induced by either cobalt chloride or desferrioxamine. The pro‐oxidants H 2 O 2 and buthionine sulfoximine down‐regulated HIF‐1α and P‐gp, whereas up‐regulation was achieved with the radical scavengers dehydroascorbate, N ‐acetylcysteine, and vitamin E. The correlation of HIF‐1α and P‐gp expression was validated by the use of hepatoma tumor spheroids that were either wild type (Hepa1) or mutant (Hepa1C4) for aryl hydrocarbon receptor nuclear translocator (ARNT), i.e., HIF‐1β. Chemical hypoxia robustly increased HIF‐1α as well as P‐gp expression in Hepa1 tumor spheroids, whereas no changes were observed in Hepa1C4 spheroids. Hence, our data demonstrate that expression of P‐gp in multicellular tumor spheroids is under the control of HIF‐1.