Expression of the major vault protein LRP in human non-small-cell lung cancer cells: Activation by short-term exposure to antineoplastic drugs

Non-small-cell lung cancer (NSCLC) cells are characterised by resistance to the toxic impact of antineoplastic drugs both in vivo and in vitro, The lu ng resistance-related protein (LRP), identical with the human major vault p rotein, is over-expressed in a variety of tumour cells characterised by int rinsic or acquired chemoresistance, We investigated the expression and cell ular localisation of LRP in 16 unselected NSCLC cell lines, immortalised br onchial epithelial cells and embryonic lung fibroblasts. All cell lines ana lysed expressed LRP mRNA, while protein expression ranged from undetectable up to high levels. Cell fractionation and immunofluorescence staining in s elected cell lines localised LRP almost exclusively to the cytoplasm. LRP w as contained in the 100,000 g pellet and absent in the soluble, cytosolic f raction and nuclei. A small proportion of LRP, however, was shown to be loo sely associated with the outside of the nuclei, Sucrose gradient equilibriu m centrifugation revealed presence of LRP exclusively in the fraction known to accumulate purified vault particles. Short-term exposure (16 hr) to sub toxic daunomycin (DM)-, and bleomycin (BM)-concentrations significantly (up to 4-fold) enhanced LRP expression in 2/4 cell lines tested. Cisplatin (CD DP) had a minor effect while vinblastine (VBL) was ineffective. At cytotoxi c conditions all drugs rather decreased than increased LRP expression, When basic LRP expression was compared with chemosensitivity, a significant cor relation was detected for resistance to CDDP but not DM, doxorubicin (DOX), etoposide (VP-16), VBL and BM, Summing up, our data suggest a role of vaul ts both in basic CDDP resistance and, additionally, in an short-term defens ive response of NSCLC cells against several other drugs, Int. J. Cancer 88: 293-300, 2000, (C) 2000 Wiley-Liss, Inc.