A very early induction of major vault protein accompanied by increased drug resistance in U-937 cells

Int J Cancer. 2002 Jan 10;97(2):149-56. doi: 10.1002/ijc.1590.

Abstract

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.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters / genetics
  • ATP-Binding Cassette Transporters / metabolism
  • Antibiotics, Antineoplastic / pharmacology*
  • Antineoplastic Agents / pharmacology
  • Cell Compartmentation
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm*
  • Heat-Shock Response
  • Hot Temperature
  • Humans
  • Mitochondrial Proteins*
  • Multidrug Resistance-Associated Proteins / genetics
  • Multidrug Resistance-Associated Proteins / metabolism
  • Neoplasm Proteins*
  • Precipitin Tests
  • RNA, Messenger / metabolism
  • RNA, Neoplasm / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Ribosomal Proteins / genetics
  • Ribosomal Proteins / metabolism
  • Saccharomyces cerevisiae Proteins*
  • U937 Cells / drug effects*
  • U937 Cells / metabolism
  • Up-Regulation
  • Vault Ribonucleoprotein Particles / biosynthesis*
  • Vault Ribonucleoprotein Particles / genetics

Substances

  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • ATP-Binding Cassette Transporters
  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • MRP2 protein, S cerevisiae
  • Mitochondrial Proteins
  • Multidrug Resistance-Associated Proteins
  • Neoplasm Proteins
  • RNA, Messenger
  • RNA, Neoplasm
  • Ribosomal Proteins
  • Saccharomyces cerevisiae Proteins
  • Vault Ribonucleoprotein Particles
  • major vault protein
  • Doxorubicin
  • multidrug resistance-associated protein 1