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 chemotherapeu tic drugs. We studied whether other genes involved in drug resistance are regulated by similar signaling pathways. Transient (up to 24 h) tr eatment of HL-60 or K562 leukemia cells with phorbol 12-myristate 13-a cetate (TPA) resulted in increased steady-state level of LRP (lung res istance-related protein) mRNA and protein. Among conventional chemothe rapeutic drugs tested, only cytarabine (Ara C) induced the LRP mRNA ex pression though Ilo increase in LRP protein was detected. LRP gene act ivation was not detectable in either H9 T-cell leukemia or in solid ca rcinoma cell lines (BT-20, ZR-75-1, and SW 1573). None of the agents i nfluenced the levels of MRP (multidrug resistance-associated protein) mRNA in any cell line tested. In HL-60 cells, the LRP activation by TP A or Ara C was sustained for at least 23 days after withdrawal of indu cing agents. bis-Indolylmaleimide I, a potent PKC inhibitor, attenuate d 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.