Hypoxic induction of apoptosis occurs through HIF-1α and accompanies mammalian sterile 20-like kinase 2 cleavage in human endometrial adenocarcinoma Ishikawa cells

Abstract

The incidence of endometrial cancer is increasing worldwide. One of the main causes of this cancer is a hormone imbalance; progesterone derivatives have been used for treatment. However, reports have shown that hypoxia plays important and possibly beneficial roles in endometrial function. Here, we show the effect of hypoxia on the proliferation of human endometrial adenocarcinoma Ishikawa cells. Hypoxia induced caspase-dependent apoptosis in Ishikawa cells. Overexpression and siRNA-mediated knockdown of hypoxia-inducible factor-1α (HIF-1α) confirmed that HIF-1α accelerates hypoxia-induced cell death. Treatment with dimethyloxalglycine, which stabilizes HIF-1α, suppressed cell proliferation. Kaplan-Meier analysis showed that the expression level of HIF-1α has a significant positive effect on the survival rate of endometrial cancer patients. In our search for cellular targets involved in hypoxic apoptosis, we noticed that mammalian sterile 20-like kinase 2 (MST2), a member of the Hippo pathway, was positively correlated with HIF-1α expression in 176 endometrial cancer patients extracted from the TCGA database. Hypoxia induced caspase-dependent MST2 cleavage. In addition, a MST2 inhibitor suppressed HIF-1α-mediated reporter activity. These results suggest HIF-1α and the Hippo signaling pathway are involved in endometrial cancer.

Keywords: Apoptosis; Endometrial cancer; Hippo signaling pathway; Hypoxia; Mammalian sterile 20-like kinase 2.