Objective: The objectives of the study were to evaluate the role of mitogen-activated protein kinase (MAPK) signaling in normal, hyperplastic, and neoplastic endometrium in relation to estrogen receptor (ER) status and to investigate whether 17β-estradiol (E2) and tamoxifen (TAM) mediate the proliferation and apoptosis of endometrial cancer cells through the MAPK pathway.
Methods: The expressions of phosphorylated and total extracellular signal-regulated kinases 1/2 (phosphorylated extracellular signal-regulated kinase 1/2 [p-ERK1/2] and total ERK1/2 [t-ERK1/2]) were analyzed with immunohistochemistry in normal, hyperplastic, and neoplastic endometrium. The expression levels of p-ERK1/2 and t-ERK1/2 in RL95-2 and KLE after stimulation by E2, progesterone (P), and TAM were detected by Western blotting. The effects of E2 and TAM in combination with MAPK pathway inhibitors on the growth and apoptosis of endometrial cancer cells were examined by the MTS assay and flow cytometry analysis.
Results: The expression level of p-ERK1/2 was significantly associated with the International Federation of Gynecology and Obstetrics stage (P = 0.0072). The ratio of phosphorylated/total ERK1/2 was higher in ER-positive endometrial cancer tissues and cells (P < 0.05). 17β-Estradiol increased ERK1/2 phosphorylation, and TAM decreased ERK1/2 phosphorylation in endometrial cancer cell lines within 30 minutes (P < 0.05). The MEK1/2 inhibitor, U0126, and the stress-activated protein kinase/c-Jun NH2-terminal kinase inhibitor, SP600125, significantly suppressed the proliferation of human endometrial cancer cell lines RL95-2 and KLE induced by E2 (P < 0.05). The level of TAM-induced apoptosis was greater in KLE than in RL95-2 cells, and the p38 cascade was involved in the TAM-induced apoptosis of both cell lines (P < 0.05).
Conclusions: The cross-talk between MAPK signaling and ER status might exert a key role in progression of endometrial cancer. Furthermore, the effects of E2 or TAM on the proliferation or apoptosis of ER-positive and ER-negative endometrial cancer cells were mediated through distinct MAPK pathways. These mechanisms might contribute to ER-specific differences in MAPK activation for molecular-target therapies in endometrial carcinoma.
- Endometrial carcinoma
- Estrogen receptor (ER)
- Mitogen-activated protein kinase (MAPK)
Statistics from Altmetric.com
The study was supported by the Chinese National Natural Science Foundation of China (30672236, 30872760, and 81072139).
The authors declare that there are no conflicts of interest.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.