Enterolactone and THBS1-3TSR synergistically inhibit ovarian cancer and suppress angiogenesis in the tumour microenvironment.

BACKGROUND AND PURPOSE: Ovarian cancer is a highly malignant disease with poor prognosis due to its insidious occurrence, early metastasis and high rate of recurrence after treatment. Enterolactone (ENL) has previously been reported to inhibit ovarian cancer in positive correlation with THBS1 expression, but the involved molecular events remain unknown. In this study, we looked into interactions between ENL and THBS1 to elucidate the mechanisms underlining their joint inhibitory effects on ovarian cancer.

EXPERIMENTAL APPROACH: We observed the suppressive effect of ENL on ovarian cancer cells by cell counting kit-8, wound healing, transwell, western blot and immunohistochemistry assays. The binding of ENL to THSB1 was assessed by molecular docking and microscale thermophoresis assays. Inhibition of malignant angiogenesis by ENL was inspected by tube formation assay and zebrafish experiment. The in vivo anticancer abilities of ENL were investigated by xenograft and allograft ovarian cancer animal models, and the fecal microbiota was analysed by metagenomics.

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RESULTS

This study demonstrated potent inhibitory effects of ENL on ovarian cancer by both in vitro and in vivo experiments. Analysis of 61 clinical samples showed a correlation between poor prognosis and low THBS1 expression. ENL affected the expression of THBS1 and other proteins such as CD36. ENL through binding with the 3TSR domain of THBS1 inhibited malignant angiogenesis and suppressed cancer progression. ENL administration could also ameliorate gut dysbacteriosis.

CONCLUSIONS AND IMPLICATIONS: ENL has potent inhibitory effects on ovarian cancer and suppresses malignant angiogenesis by binding to THBS1-3TSR. ENL ameliorates gut dysbacteriosis.