Tamoxifen inhibits cell proliferation via mitogen-activated protein kinase cascades in human ovarian cancer cell lines in a manner not dependent on the expression of estrogen receptor or the sensitivity to cisplatin.
Although tamoxifen (TAM), which is widely used in the treatment of breast cancer, also has a beneficial effect on cisplatin-refractory ovarian cancer, the biological mechanism of this effect has remained obscure. TAM, besides its action as an antiestrogen, also inhibits cell proliferation of estrogen receptor (ER)-negative cells by an unknown mechanism. Therefore, we examined the roles of the MAPK family in the antiproliferative effect of TAM on cisplatin-resistant Caov-3, which expresses ER and cisplatin-sensitive A2780, which does not express ER. The number of viable cells was reduced by TAM dose-dependently. TAM induced the activation of ERK, c-Jun N-terminal protein kinase (JNK), and p38 with different time courses. PD98059 canceled the reduction of the number of viable cells by 1 microM TAM and inhibited the TAM-induced cell-cycle arrest at the G(1) phase and dephosphorylation of the retinoblastoma protein. Either expression of dominant-negative JNK or pretreatment with SB203580 canceled the reduction of the number of viable cells by 5 microM TAM and inhibited the apoptotic nuclear changes and the cleavage of poly (ADP-ribose) polymerase induced by TAM. These results provide evidence that whereas the ERK cascade is involved in the induction of cell-cycle arrest at the G(1) phase by lower concentrations of TAM, the JNK or p38 cascade is involved in the induction of apoptosis by higher concentrations of TAM in both types of cells.
Mabuchi
Seiji
S
Departmentof Obstetrics and Gynecology, Osaka University Medical School, Suita, Osaka 565-0871, Japan.
Ohmichi
Masahide
M
Kimura
Akiko
A
Ikebuchi
Yoshihide
Y
Hisamoto
Koji
K
Arimoto-Ishida
Emi
E
Nishio
Yukihiro
Y
Takahashi
Kazuhiro
K
Tasaka
Keiichi
K
Murata
Yuji
Y
D000231:Adenocarcinoma, Papillary; D000970:Antineoplastic Agents / Q000494:pharmacology; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010051:Ovarian Neoplasms; D018384:Oxidative Stress / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics*; D013629:Tamoxifen / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases
D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D000975:Antioxidants; D004791:Enzyme Inhibitors; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D011960:Receptors, Estrogen; D013629:Tamoxifen; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; D002945:Cisplatin; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one