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Submitted on June 25, 2003
Accepted on September 12, 2003
1 Department of Obstetrics and Gynecology, Osaka University Medical School, 2-2, Yamadaoka, Suita, Osaka 565-0871, Japan.
* To whom correspondence should be addressed. E-mail: masa{at}gyne.med.osaka-u.ac.jp.
The influence of postoperative estrogen replacement therapy on the sensitivity of ovarian cancer to paclitaxel remains elusive. We examined whether estrogen affects paclitaxel-induced apoptosis in the Caov-3 human ovarian cancer cell line, which expresses ER. 17
-estradiol (E2) significantly reversed the paclitaxel-induced apoptosis and reduction of cell viability, and a highly selective ER antagonist, ICI182,780 and a phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, attenuated the reversal effect of E2 on paclitaxel-induced apoptosis and reduction of cell viability. E2 significantly induced the phosphorylation of Akt. Akt and apoptosis signal-regulating kinase 1 (ASK1) were physically associated and E2 induced the phosphorylation of ASK1 at Ser-83, which is a consensus Akt phosphorylation site. We confirmed a previous report showing that paclitaxel induces cell damage via the ASK1-JNK cascade. E2 inhibited the paclitaxel-induced JNK activation, and the E2-induced inhibition of the paclitaxel-induced JNK activation was attenuated in cells either treated with ICI182,780 or LY294002 or transfected with ASK1S83A, in which a consensus Akt phosphorylation site at serine 83 was converted to alanine. The inhibitory effect of E2 on the paclitaxel-induced reduction of cell viability and apoptosis was diminished in cells transfected with ASK1S83A. These results indicate that E2 inhibits paclitaxel-induced cell damage by inhibiting JNK activity via phosphorylation of Akt-ASK1. Thus, treatment of ovarian cancer with paclitaxel might be less effective in the setting of postoperative estrogen replacement therapy.
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