Inhibition of tetrandrine on epidermal growth factor-induced cell transformation and its signal transduction.
BACKGROUND
The mouse epidermal JB6 cell system is a model for studying tumor promotion. We used the JB6 Cl 41 cell line to examine the mechanism of the anti-tumor-promoting effect of tetrandrine, an alkaloid isolated from Stephania tetrandra S Moore.


METHODS
The anti-tumor-promoting effect of tetrandrine was evaluated by assay of inhibition of epidermal growth factor (EGF)-induced transformation of JB6 Cl 41 cells in soft agar. The activity of activator protein-1 (AP-1), a transcription factor, was analyzed using the AP-1-dependent reporter assay. Phosphorylation of extracellular-signal regulated kinases (ERKs) and Akt, a pivotal effector of phosphatidylinositol 3-kinase (P13K), was detected by Western blotting.


RESULTS
Tetrandrine significantly blocked EGF-induced cell transformation, attenuated EGF-induced AP-1 activation, and inhibited phosphorylation of ERKs, which regulates AP-1 activation. It also tended to suppress EGF-induced Akt phosphorylation.


CONCLUSIONS
Our results indicate that tetrandrine inhibits EGF-induced transformation of JB6 cells by blocking the activation of ERKs, AP-1 and Akt.
Nomura
Masaaki
M
Department of Clinical Pharmacology, Faculty of Pharmaceutical Sciences, and Hokuriku University, Kanazawa, Japan.
Yamazaki
Rina
R
Takaya
Makiko
M
Kikuchi
Minoru
M
Takahashi-Nishioka
Tatsuo
T
Akiyama
Kiyoshi
K
Akiyama
Noriko
N
Moritani
Shuzo
S
Kobayashi
Shinjiro
S
D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D044182:Benzylisoquinolines / Q000494:pharmacology*; D002460:Cell Line; D002461:Cell Line, Transformed; D002471:Cell Transformation, Neoplastic / Q000139:chemically induced / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004815:Epidermal Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018808:Transcription Factor AP-1 / Q000378:metabolism
D000470:Alkaloids; D044182:Benzylisoquinolines; D018808:Transcription Factor AP-1; C009438:tetrandrine; D004815:Epidermal Growth Factor; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases