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

• Published in: Cancer science Vol. 109; no. 4; pp. 1032 - 1043
• Main Authors: Shi, Kun, Wang, Qiong, Su, Yao, Xuan, Xingcui, Liu, Yaqiong, Chen, Weiwei, Qian, Yuanmin, Lash, Gendie E.
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01.04.2018; John Wiley and Sons Inc
• Subjects: Apoptosis; Apoptosis - physiology; Autophagy; Autophagy - physiology; Body mass index; Carcinoma; Cell Line, Tumor; Cell migration; Cell Movement - physiology; Cell proliferation; Cell Proliferation - physiology; Chromatography; Disease; Endometrial cancer; Endometrial Neoplasms - metabolism; Endometrial Neoplasms - pathology; Endometrium; Female; Health care; Humans; indoleacrylic acid; Indoles - metabolism; Kinases; Mass spectrometry; Metabolism; Metabolites; Metabolome - physiology; Metabolomics; Metabolomics - methods; Metastasis; Middle Aged; Neoplasm Invasiveness - pathology; Original; Patients; Phagocytosis; Phenylalanine; Phenylalanine - metabolism; Phosphocholine; Platelet Activating Factor - analogs & derivatives; Platelet Activating Factor - metabolism; Platelet-activating factor; platelet‐activating factor‐16; Scientific imaging; Studies; Tryptophan; Tryptophan - metabolism; Tumor cell lines; Tumor necrosis factor; Tumor Necrosis Factor-alpha - metabolism; Tumors; Urine; Uterine cancer; Womens health; China; endometrial cancer; platelet-activating factor-16; phenylalanine; phosphocholine; indoleacrylic acid
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/cas.13532

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. Serum metabolomics was performed in endometrioid endometrial cancer patients and healthy volunteers. Four metabolites were selected from the differentially expressed metabolites for the function analyses and they had differing effects on tumour cell function.