Activation of the LRP (lung resistance-related protein) gene by short-term exposure of human leukemia cells to phorbol ester and cytarabine.
Treatment-induced secondary drug resistance of tumor cells is a major cause of relapsed disease and therapeutic failure in cancer patients. It has been shown that the expression of the multidrug resistance MDR1/P-glycoprotein gene could be induced by short-term in vitro exposure of cells to protein kinase C (PKC) agonists or different chemotherapeutic drugs. We studied whether other genes involved in drug resistance are regulated by similar signaling pathways. Transient (up to 24 h) treatment of HL-60 or K562 leukemia cells with phorbol 12-myristate 13-acetate (TPA) resulted in increased steady-state level of LRP (lung resistance-related protein) mRNA and protein. Among conventional chemotherapeutic drugs tested, only cytarabine (Ara C) induced the LRP mRNA expression though no increase in LRP protein was detected. LRP gene activation was not detectable in either H9 T-cell leukemia or in solid carcinoma cell lines (BT-20, ZR-75-1, and SW 1573). None of the agents influenced the levels of MRP (multidrug resistance-associated protein) mRNA in any cell line tested. In HL-60 cells, the LRP activation by TPA or Ara C was sustained for at least 23 days after withdrawal of inducing agents. bis-Indolylmaleimide I, a potent PKC inhibitor, attenuated TPA-induced LRP activation. In contrast, the inhibitor had no effect on the LRP induction by Ara C. These data indicate that the LRP gene can be activated by different mechanisms, some of which involve PKC.
Department of Pathology, Rush Presbyterian St. Luke's Medical Center, Chicago, IL 60612, USA.
P G
PG
Komarov
A A
AA
Shtil
O
O
Holian
L
L
Tee
L
L
Buckingham
E B
EB
Mechetner
I B
IB
Roninson
J S
JS
Coon
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis / Q000235:genetics; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002273:Carcinogens / Q000494:pharmacology*; D003561:Cytarabine / Q000494:pharmacology*; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D019450:Genes, MDR / Q000187:drug effects; D018922:HL-60 Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D020014:K562 Cells / Q000187:drug effects / Q000378:metabolism; D007942:Leukemia, Experimental / Q000235:genetics* / Q000378:metabolism*; D015458:Leukemia, T-Cell / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics*; D011493:Protein Kinase C / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured / Q000187:drug effects; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000964:Antimetabolites, Antineoplastic; D002273:Carcinogens; D003561:Cytarabine; D009363:Neoplasm Proteins; D011493:Protein Kinase C; D012333:RNA, Messenger; D013755:Tetradecanoylphorbol Acetate; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein