Paclitaxel and ceramide synergistically induce cell death with transient activation of EGFR and ERK pathway in pancreatic cancer cells.
The molecular and cellular mechanism of the development of pancreatic cancer is under constant and intensive study, and yet the cure is still out of reach. While surgical treatment is optional, conventional chemotherapy or chemo-radiotherapy remains the best choice. Among others, paclitaxel is proven to be a popular and, to a certain extent, effective chemotherapy agent. We proposed that the combination of paclitaxel and membrane permeable ceramide would enhance the fatality of cancer cells, and reported that the combination increased cell death of both head and neck and leukemic cancer cells. In this study, we treated pancreatic cancer cells (L3.6 cells) with paclitaxel and ceramide at the concentrations of clinical relevance, and treatment was then followed up with an investigation of the molecular mechanism of the synergism of paclitaxel and ceramide. The results of Western blot analysis indicated that the combo synergistically induced ERK and JNK phosphorylation, but not p38 and Akt phosphorylation. We also found that the combination (combo) induced EGFR phosphorylation in a synergistic manner. Furthermore, we observed 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, U126. Taken together, our results demonstrated that the combination of paclitaxel and ceramide synergistically induced pancreatic cancer cell death through differential activation of EGFR-mediated MAP kinases. EGFR and ERK inhibitors may further enhance the paclitaxel and ceramide effect.
Qiu
Lihua
L
Department of OB/GYN, Renji Hospital, Shanghai Jiaotong University, Shanghai 200001, P.R. China.
Zhou
Changlin
C
Sun
Yun
Y
Di
Wen
W
Scheffler
Erica
E
Healey
Sarah
S
Wanebo
Harold
H
Kouttab
Nicola
N
Chu
Wenming
W
Wan
Yinsheng
Y
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017209:Apoptosis; D016923:Cell Death; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D020935:MAP Kinase Signaling System; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D017239:Paclitaxel / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000378:metabolism*; D010766:Phosphorylation; D000077022:Survivin; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C107489:BIRC5 protein, human; D002518:Ceramides; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D017239:Paclitaxel