Export pu
mps often li
mit the usefulness of anticancer drugs. Here we investigated the effect of cisplatin on the expression of ABC proteins in hu
man colon cancer cells. Short-ter
m incubation of Caco-2 and LS174T cells with cisplatin resulted in up-regulation of several ABC pu
mps, in particular MRP2 and BCRP. In partially cisplatin-resistant cells (LS174T/R) obtained by long-ter
m exposure to cisplatin, MRP2 and BCRP up-regulation was
more
marked. This was further enhanced when these cells were cultured under
maintained sti
mulation with cisplatin. The MRP2 pro
moter (MRP2pr) was cloned, and partially deleted constructs linked to reporter genes were generated. Transfection of LS174T and LS174T/R cells with these constructs revealed the ability of cisplatin to activate MRP2pr. The intensity of this response was dependent on the conserved MRP2pr region. Basal MRP2pr activity was higher in LS174T/R cells, in which the expression of the transcription factors c/EBP尾, HNF1伪, HNF3尾, and HNF4伪, but not PXR, p53, c-Myc, AP1, YB-1, NRF2, and RAR伪 was enhanced. Up-regulation was particularly high for FXR (200-fold) and SHP (50-fold). In LS174T/R cells, GW4064 induced the expression of FGF19, SHP, OST伪/尾, but not MRP2 and BCRP, although the sensitivity of these cells to cisplatin was further reduced. In LS174T cells, GW4064-induced che
moresistance was seen only after being transfected with FXR+RXR, when BCRP, but not MRP2, was up-regulated. Protection of LS174T cells against cisplatin was
mi
micked by transfection with BCRP. In conclusion, in colon cancer cells, cisplatin treat
ment enhances che
moresistance through FXR-dependent and FXR-independent
mechanis
ms involving the expression of BCRP and MRP2, respectively.
Keywords:
ABC proteins; mor+drugs&qsSearchArea=searchText">antitumor drugs; cancer; colon; moter&qsSearchArea=searchText">promoter