TITLE:
Response of Subcutaneous Xenografts of Endometrial Cancer in Nude Mice to Inhibitors of Phosphatidylinositol 3-Kinase/Akt and Mitogen-Activated Protein Kinase (MAPK) Pathways: An Effective Therapeutic Strategy for Endometrial Cancer
AUTHORS:
Ruixia Guo, Xinyan Wang, Ruifang Zhang, Huirong Shi, Yuhuan Qiao, Wenjing Yun, Xin Ge, Yan Lin, Jia Lei
KEYWORDS:
Extracellular-Regulated Kinase (ERK), Proto-Oncogene Proteins, Akt, ERK Pathway Inhibitor, PD98059, Phosphatidylinositol-3-Kinase Pathway Inhibitor, LY294002, Endometrial Cancer Cell, Estrogen Receptor
JOURNAL NAME:
Journal of Cancer Therapy,
Vol.6 No.12,
November
27,
2015
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.