Down-regulation of growth factor-stimulated MAP kinase signaling in cytotoxic drug-resistant human neuroblastoma cells

The mitogen-activated protein kinase (MAPk) signaling pathway, which plays a critical role in the proliferation of mammalian cells. is frequently up-r egulated in human tumors and may contribute to the transformed phenotype. S ince a major limitation of current cancer chemotherapy is prevalent resista nce to cytotoxic drugs. this study determined whether alterations in growth factor signaling through MAPk may contribute to this phenomenon in human n euroblastoma cell lines. Drug-resistant SKNSH cell lines were established b y long-term incubation with increasing concentrations to 10(-6) M doxorubic in (SKNSH rDOX6) or MDL 28842 (SKNSH rMDL6). The expression of epidermal gr owth factor receptor (EGFR) and epidermal growth factor (EGF)-induced EGFR tyrosine phosphorylation were lower in drug-resistant SKNSH cells than thei r wild-type counterparts. In SKNSH rDOX6 cells, decreased activation and re duced nuclear translocation of MAPk in response to EGF, or lysophosphatidic acid (LPA), or phorbol 12-myristate 13-acetate (PMA), were observed. In SK NSH rMDL6 cells, although MAPk could be activated to wild-type levels by li gand stimulation. the translocation of acticle MAPk to the nucleus was also reduced. These results suggest that resistance to cytotoxic drugs in human neuroblastoma cell lines is associated with a decrease in growth factor si gnaling through the MAPk pathway. (C) 2001 Elsevier Science Inc. All rights reserved.