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Synthetic ALPs, e.g., Et‐18‐OCH₃ and HePC, are anticancer agents that accumulate in cell membranes, where they interfere with lipid‐mediated signal transduction. We previously reported that ALPs, when added at micromolar concentrations (5–25 μM), inhibit growth factor–induced MAPK/ERK activation and enhance radiation‐induced apoptosis. We now show that, at nanomolar doses (10–500 nM), ALPs activate the MAPK/ERK pathway in A431 cells without stimulating cell proliferation. Strikingly, ALPs (500 nM) also trigger rapid clustering and internalization of the EGFR in A431 cells. Tyrphostin AG1478, an EGFR tyrosine kinase inhibitor, blocks ALP‐induced MAPK/ERK activation but not EGFR internalization. We found no evidence for ALPs acting via G protein–coupled receptors and/or transactivation of EGFRs, as determined by calcium mobilization, EGFR phosphorylation and Grb2 binding assays. Since …