Estrogen Inhibits Paclitaxel-Induced Apoptosis via the Phosphorylation of Apoptosis Signal-Regulating Kinase 1 in Human Ovarian Cancer Cell Lines

Abstract

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 estrogen receptor. 17beta-Estradiol (E2) significantly reversed the paclitaxel-induced apoptosis and reduction of cell viability, and a highly selective estrogen receptor antagonist, ICI182,780, and a phosphatidylinositol 3-kinase 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 serine-83, which is a consensus Akt phosphorylation site. We confirmed a previous report showing that paclitaxel induces cell damage via the ASK1-c-Jun N-terminal protein kinase (JNK) cascade. E2 inhibited the paclitaxel-induced JNK activation, and the E2-induced inhibition of the paclitaxel-induced JNK activation was attenuated in cells treated with either 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.

Inhibition of NADPH oxidase 4 activates apoptosis via the AKT/apoptosis signal-regulating kinase 1 pathway in pancreatic cancer PANC-1 cells

“…We therefore propose that Nox4-dependent cell survival signaling is mediated by the AKT-ASK1 kinase cascade, and that antagonizing this signaling pathway by DPI or siNox4RNAs results in activation of apoptosis. Similarly, the anticancer drug paclitaxelinduced apoptosis of ovarian cancer cells is mediated by negative regulation of AKT-ASK1 phosphorylation signaling (Mabuchi et al, 2004) and AKT activation by H 2 O 2 confers protection against apoptosis (Wang et al, 2000). It has been reported that ROS oxidize thioredoxin (TRX), a negative regulator of ASK1, and thereby dissociate TRX from pre-existing TRX-ASK1 complexes, resulting in the activation of ASK1 and the subsequent ASK1-dependent apoptosis (Saitoh et al, 1998).…”

Downregulation of Aurora-A overrides estrogen-mediated growth and chemoresistance in breast cancer cells

“…(Anand et al 2003, Yang et al 2006. Also known is that estrogen protects breast and ovarian cancer cells from taxol-induced apoptosis (Mabuchi et al 2004, Sui et al 2007. Based on our data that Aurora-A downregulation can override E 2 -induced growth and transformation, we speculated that downregulation of Aurora-A might counteract the estrogen-mediated decrease in Doc sensitivity as well.…”

“…Alternatively, in addition to being pro-proliferative, estrogen has been shown to be a survival factor also. Estrogen has been shown to abrogate the apoptotic response of ovarian cancer cells to paclitaxel (Mabuchi et al 2004) and ER-positive breast cancer cells tend to be more resistant to anti-neoplastic drugs such as paclitaxel and Doc (Sui et al 2007). On the other hand, Aurora-A has been emerging as on anti-cancer target for reasons related to its role in cell cycle regulation, checkpoint evasion, centrosome amplification, and aneuploidy.…”

“…The exact mechanism by which Doc exerts its cytotoxic effect on cancer cells is not clearly understood. It has been shown that paclitaxel, another member of the taxane family, has been shown to exert its apoptotic effect in ovarian cancer cells through phosphorylation of Akt and E 2 significantly reduced the phosphorylation of Akt (Mabuchi et al 2004), providing a mechanistic explanation for the anti-apoptotic role of E 2 . Recently, it has also been observed that Aurora-A activates Akt and induces chemoresistance in a p53-dependent manner in ovarian cancer cells (Yang et al 2006).…”

Impact of post-operative hormone replacement therapy on life quality and prognosis in patients with ovarian malignancy

“…In vitro experiments have yielded inconsistent results regarding the estrogen stimulation of cancer cell proliferation. Certain in vitro experiments have shown that estrogen is capable of stimulating the proliferation of malignant cells (12,13), whereas results of other studies showed tumor cell growth inhibition by estrogen (14), and yet other authors found no effect of estrogen on malignant cell growth (15,16). Furthermore, current scientific evidence does not show HRT to adversely affect outcome in patients following treatment for ovarian malignancy (6,16).…”