Multidrug resistance proteins MRP3, MRP1, and MRP2 in lung cancer: Correlation of protein levels with drug response and messenger RNA levels

Previously (L, C. Young st al., Clin, Cancer Res., 5: 673-680, 1999), we fo und, in a panel of 23 lung cancer cell lines that had not been selected for irt vivo drug resistance, that the mRNA levels of MRP3 and MRP1, two membe rs of the ATP-binding cassette superfamily of transport proteins, correlate d with resistance to doxorubicin, vincristine, VP-16, and cis-diamminedicho loroplatinum(II). To extend these studies, we measured multidrug resistance protein (MRP)1, MRP2, and MRP3 protein levels in a panel of 30 lung cancer cell lines that included the original 23 cell lines as well as an addition al 7 unselected lung cancer cell lines. In the case of MRP3, a polyclonal a ntibody was developed that was found to be a sensitive reagent for the dete ction of MRP3 by Western blot analysis, We found good agreement in the orig inal 23 cell lines between the cognate mRNA and protein levels for MRP1, MR P2, and, especially, MRP3 (r, 0.852), supporting the use of semiquantitativ e PCR to predict MRP1, MRP2, and MRP3 protein levels in patient samples. Th ere mere also strong correlations between the mRNA. and protein levels of M RP3 and MRP1, which suggested that these genes might be expressed in a coor dinate manner. h;MRP3, MRP1, and MRP2 protein levels mere higher in the non -small cell lung cancer (NSCLC) than in the SCLC cell lines and, in additio n, MRP3 and MRP2 were detected almost exclusively in the NSCLC cell lines. Finally, we found that both MRP3 and MRP1, but not MRP2, protein levels cor related with decreased sensitivity of these lung cancer cell lines to doxor ubicin, VCR, VP-16, and cis-diamminedichaloroplatinum(Ir). These findings a re consistent with our hypothesis that both MRP3 and MRP1 are components of the multifactorial multidrug resistance phenotype of lung cancer and that MRP3 contributes to the intrinsic resistance of NSCLC cells.