Identification and functional analyses of differentially expressed metabolites in early stage endometrial carcinoma

Abstract

Diagnosis of endometrial cancer is primarily based on symptoms and imaging, with early-stage disease being difficult to diagnose. Therefore, development of potential diagnostic biomarkers is required. Metabolomics, a quantitative measurement of the dynamic metabolism in living systems, can be applied to determine metabolite profiles in different disease states. Here, serum metabolomics was performed in 46 early stage endometrial cancer patients and 46 healthy volunteers. In addition, the effect of identified metabolites on tumor cell behavior (invasion, migration, proliferation, apoptosis and autophagy) was examined in endometrial cancer cell lines. Compared with controls, phenylalanine, indoleacrylic acid (IAA), phosphocholine and lyso-platelet-activating factor-16 (lyso-PAF) were differentially detected in patients. Functional analyses demonstrated that IAA, PAF and phenylalanine all dose-dependently inhibited tumor cell invasion and migration, and suppressed cell proliferation. PAF also induced tumor cell apoptosis and autophagy, while phenylalanine had no effect on apoptosis or autophagy. IAA triggered apoptosis and had a biphasic effect on autophagy: inhibiting autophagy with doses <1 mmol/L but inducing at 1 mmol/L. Interestingly, the alterations in proliferation, apoptosis and autophagy caused by 1 mmol/L IAA, were all reversed by the concomitant treatment of tryptophan (100 μmol/L). Phosphocholine inhibited tumor cell invasion and migration, and promoted cell proliferation and autophagy, all in a dose-dependent manner. Phosphocholine also protected cells from TNF-α-induced apoptosis. In conclusion, 4 serum metabolites were identified by serum metabolomics in endometrial cancer patients and functional analyses suggested that they may play roles in modulation of tumor cell behavior, although their exact mode of action still needs to be determined.

Keywords: endometrial cancer; indoleacrylic acid; phenylalanine; phosphocholine; platelet-activating factor-16.