Abstract
Objective: This study was designed to explore whether inhibition of the extracellular-regulated kinase (ERK) and phosphatidylinositol-3-kinase (PI3K) signaling pathways can inhibit the growth of xenografts of endometrial cancer cell lines with different estrogen receptors (ER) profiles in vivo and to provide preliminary laboratory basis for the probability of endometrial adenocarcinoma treatment with blockage of the two pathways, especially to endometrial cancer with low ER status. Methods: Human endometrial cancer Ishikawa bearing ER and HEC-1Awith low ER status cells were subcutaneously injected into BALB/c nude mice to establish endometrial cancer xenograft tumor models. The effects of PI3K/Akt inhibitor LY294002, MAPK/ERK1/2 inhibitor PD-98059 and their combinations on the growth of the xenograft tumors and apoptotic state of Ishikawa and HEC-1Acells were tested in vivo using the inhibitory rate, the terminal deoxynucleotidyl transferase-mediated nick-end labeling assay, H/E-stain. Western blot analysis was used to detect the alterations of activated ERK (P-ERK) and AKT (P-AKT) during this process. Results: LY294002, a PI3K/Akt pathway inhibitor, induced significant suppression in the growth of both Ishikawa and HEC-1Acell xenograft tumors, concomitant with increased apoptosis in xenografts as evidenced by TUNEL. A similar effect was also observed when the MAPK/ERK1/2 signaling pathway was inhibited by PD98059. Concurrent inhibition of the PI3K/Akt and MAPK/ERK1/2 pathways showed enhanced anti-tumor effects in vivo as indicated by increased apoptosis. At the same time, the levels of P-ERK and P-AKT in both xenograft tumors decreased, and their levels in combination group was the lowest. Conclusions: PD98059, LY294002 and their combinations showed remarkable inhibitory effects on xenograft tumors of endometrial carcinoma cell lines with different expression status of ER in vivo through blockage of PI3K/Akt and MAPK/ERK1/2 signaling pathways. This suggests that targeting these pathways may be an effective therapeutic strategy against endometrial carcinomas, especially for ER-negative cancers which show poor response to endocrinal therapy.
Highlights
Endometrial carcinoma is one of the most common gynecological carcinomas
We found that blocking the Mitogen-Activated Protein Kinase (MAPK)/extracellular-regulated kinase (ERK) and PI3K/Akt could effectively reduce tumor growth and enhance apoptosis in xenografts of Ishikawa and HEC-1A cell lines, suggesting that these pathways might be important targets for treating endometrial cancers
To determine whether the effects of PD98059 and LY294002 on xenograft tumors of endometrial carcinoma cells were correlated with estrogen receptor (ER) status, we established xenograft tumor models with Ishikawa and HEC-1A cell lines that have distinct ER profiles (Figure 1)
Summary
Two types of endometrial cancers have been described based on clinical and histopathology features. Type I endometrial carcinomas are usually found in patients with a high estrogen level that is unopposed by progestin. These well-differentiated tumors have good response to endocrinal therapy and a good prognosis. Type II is generally associated with the normal estrogen state and usually shows poor response to endocrinal therapy. These tumors are usually poorly differentiated, highly malignant and present bad prognosis. It is necessary to find a new strategy for the treatment of endometrial cancers, especially for type II
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