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A very early induction of major vault protein accompanied by increased drug resistance in U‐937 cells
Author(s) -
Hu Yi,
Stephen Andrew G.,
Cao Jin,
Tanzer Lee R.,
Slapak Christopher A.,
Harrison Steadman D.,
Devanarayan Viswanath,
Dantzig Anne H.,
Starling James J.,
Rome Leonard H.,
Moore Robert E.
Publication year - 2001
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.1590
Subject(s) - vault (architecture) , doxorubicin , biology , etoposide , multiple drug resistance , messenger rna , microbiology and biotechnology , drug resistance , mitoxantrone , protein biosynthesis , cancer research , gene , chemotherapy , biochemistry , genetics , structural engineering , engineering
U‐937 human leukemia cells were selected for resistance to doxorubicin in the presence or absence of a specific drug modulator that inhibits the activity of P‐glycoprotein (Pgp), encoded by the multidrug‐resistance gene (MDR1). Parental cells expressed low basal levels of the multidrug‐resistance‐associated gene (MRP1) and major vault protein (MVP) mRNAs and no MDR1 mRNA. Two doxorubicin‐resistant cell lines were selected. Both drug‐resistant cell lines upregulated the MVP mRNA level 1.5‐fold within 1 cell passage. The MVP mRNA level continued to increase over time as the doxorubicin selection pressure was increased. MVP protein levels generally paralleled the mRNA levels. The 2 high molecular weight vault protein mRNAs were always expressed at constitutive levels. Fully formed vault particles consisting of the MVP, the 2 high molecular weight proteins and the vault RNA assembled and accumulated to increased levels in drug‐selected cells. MVP induction is therefore the rate‐limiting step for vault particle formation in U‐937 cells. By passage 25 and thereafter, the selected cells were resistant to doxorubicin, etoposide, mitoxantrone and 5‐fluorouracil by a pathway that was independent of MDR1, MRP1, MRP2 and breast cancer resistance protein. In summary, U‐937 doxorubicin‐selected cells are programmed to rapidly upregulate MVP mRNA levels, to accumulate vault particles and to become multidrug resistant. © 2002 Wiley‐Liss, Inc.