The Role of Downstream Signaling Pathways of the Epidermal Growth Factor Receptor for Artesunate's Activity in Cancer Cells

Epidermal growth factor (EGF) and its receptor (EGFR) as well as the EGFR-coupled Ras>Raf>MEK>ERK pathway are known to affect the survival of cancer cells upon chemotherapeutic treatment. In the present investigation, we analyzed the role of EGFR signaling pathways for the activity of artesunate towards cancer cells. The microarray-based mRNA expression of genes involved in EGFR signaling pathway was correlated with the 50% inhibition concentrations (IC50) of 55 tumor cell lines for artesunate. The log10IC(50) values were in a range of -6.609 to -4.0M. Candidate genes identified by this approach were then experimentally validated by transfecting cell lines with corresponding cDNA vectors and treating them with artesunate. Indeed, we observed that the Ras>Raf>MEK>ERK pathway is an important signaling route for the response of tumor cells to artesunate. As exemplarily shown for artesunate, the application of such a combined approach to identify signal transduction pathways involved in the response of tumor cells to cytotoxic compounds might foster the development of novel molecular targeted therapies for cancer treatment.