Targeted inhibition of transient activation of the EGFR-mediated cell survival pathway enhances paclitaxel-induced ovarian cancer cell death.
Emerging studies have suggested that transient activation of the cell survival pathway may be the strategy for cancer cells to fight against chemotherapy and eventually mysteriously evade paclitaxel-induced cell death. Modulation of the EGFR-mediated survival pathway in addition to the utilization of paclitaxel renders a promise of better clinical management. The objective of this study was to understand the molecular mechanism of transient induction of EGFR-mediated cell survival by paclitaxel. We utilized ovarian cancer cell line, Caov3, cells to investigate the effect of paclitaxel on EGFR-mediated MAP kinase and AKT activation, and the expression of survivin. We found that paclitaxel transiently induced EGFR phosphorylation and ERK and AKT activation but not JNK and p38. Paclitaxel-induced ERK and AKT activity was inhibited by the EGFR inhibitor, PD153035; ERK inhibitor, U0126; and PI3 kinase inhibitor, LY294002, respectively. We observed that paclitaxel transiently induced expression of survivin in the early hours of treatment. Paclitaxel-induced survivin expression was inhibited by the EGFR inhibitor, PD153035. Inhibitors of EGFR, ERK and PI3 kinase all enhanced paclitaxel-induced cell death. We conclude that paclitaxel transiently transactivates EGFR, leading to activation of cell survival factors, such as ERK and AKT, and expression of survivin, which are all inclusively accountable for ovarian cancer cell resistance to paclitaxel treatment. A combination of these inhibitors with paclitaxel may be a better option for ovarian cancer treatment.
Qiu
Lihua
L
OB/GYN Department, Renji Hospital, Shanghai Second Medical University, P.R. China.
Di
Wen
W
Jiang
Qin
Q
Scheffler
Erica
E
Derby
Steven
S
Yang
Jian
J
Kouttab
Nicola
N
Wanebo
Harold
H
Yan
Bingfang
B
Wan
Yinsheng
Y
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects* / Q000502:physiology; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D017239:Paclitaxel