Paclitaxel and Ceramide synergistically induce cell death with transient activation of EGFR and ERK pathway in pancreatic cancer cells

Abstract

Previously, we proposed that combination of paclitaxel and membrane permeable ceramide would enhance the killing of cancer cells, and we reported that combination did increase cell death of head and neck, and leukemic cancer cells. In this study, we used paclitaxel and ceramide at the concentration of clinical relevance to treat pancreatic cancer cells (L3.6 cells). To further understand the mechanism of the synergism of paclitaxel and ceramide, we treated cells with paclitaxel, ceramide, or combo. Westernblot analysis results indicated that the combo synergistically induced ERK and JNK but not P38 and Akt phosphorylation. We also found that the combo induced EGFR phosphorylation in a synergistic manner. Furthermore, we found that paclitaxel, ceramide, or combo‐induced EGFR phosphorylation was inhibited by EGFR inhibitor, PD153035, while paclitaxel, ceramide, or combo‐induced JNK and ERK phosphorylation was blocked by EGFR inhibitor, PD153035 and ERK inhibitor, U0126. Taken together, our results have shown that combination of paclitaxel and ceramide synergistically induced pacreatic cancer cell death through differential activation of EGFR‐mediated MAP kinases. EGFR and ERK inhibitors may further enhance the paclitaxel and ceramide effect.