ERK activation and subsequent RB phosphorylation are important determinants of the sensitivity to paclitaxel in lung adenocarcinoma cells.
Paclitaxel is used frequently in the treatment of advanced non-small cell lung cancer. This study was carried out in order to determine the role of extracellular signal-regulated kinases (ERK) and retinoblastoma protein (pRB) in the governing mechanism resistance to paclitaxel using two lung adenocarcinoma cell lines with differing sensitivities. In paclitaxel-sensitive Ma-10 cells, treatment with paclitaxel induced pRB phosphorylation at Ser795 and ERK activation. In contrast, in paclitaxel-resistant Ma-31 cells, paclitaxel dephosphorylated pRB at Ser795 without affecting ERK activity. A specific ERK inhibitor, PD98059, blocked paclitaxel-induced ERK activation and pRB phosphorylation at Ser795 in Ma-10 cells. Furthermore, PD98059 inhibited cell cycle progression during paclitaxel treatment, the accumulation of sub-G1 population, and the cytotoxic effect by paclitaxel in Ma-10 cells, suggesting that ERK activation by paclitaxel, subsequent pRB phosphorylation, and the cell cycle progression during paclitaxel treatment are important determinants of sensitivity to paclitaxel. These observations raise the possibility that the promotion of cell cycle during the exposure of lung cancer cells to paclitaxel may sensitize resistant cells to paclitaxel.
Suyama
Hisashi
H
Division of Blood Transfusion, Faculty of Medicine, Tottori University, Yonago 683-8504, Japan.
Igishi
Tadashi
T
Sano
Hiroyuki
H
Matsumoto
Shingo
S
Shigeoka
Yasushi
Y
Nakanishi
Hirofumi
H
Endo
Masahiro
M
Burioka
Naoto
N
Hitsuda
Yutaka
Y
Shimizu
Eiji
E
D000230:Adenocarcinoma / Q000188:drug therapy / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D016193:G1 Phase / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D017239:Paclitaxel / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D016160:Retinoblastoma Protein / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000972:Antineoplastic Agents, Phytogenic; D004791:Enzyme Inhibitors; D016160:Retinoblastoma Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D017239:Paclitaxel