Complement-dependent cytotoxicity (CDC) is critical for tumor cell proliferation. Previous work has revealed that epalrestat (EPA), an inhibitor of aldose reductase, plays a crucial role in tumor cell proliferation. However, whether CDC is involved in EPA-mediated inhibition of cancer cell proliferation remains unclear. This study evaluates reactive oxygen species (ROS) levels, 5-ethynyl-2'-deoxyuridine (EdU) incorporation, and Cell Counting Kit-8 assay to determine the effect of EPA on cell proliferation in colorectal cancer cells. Quantitative real-time PCR, immunoblotting, rescue experiments combined with luciferase reporter assay, and chromatin immunoprecipitation (ChIP) assay were performed to explore the mechanism of EPA on CDC. In the present study, we observed that EPA significantly downregulates cell proliferation characterized by enhanced ROS levels and reduced EdU + positive cells, which was attributed to the decreased CD46 expression. Ectopic CD46 expression reversed the above EPA-induced phenomenon. Mechanistically, EPA treatment suppressed protein kinase D (PKD)/signal transducer and activator of transcription 3 (STAT3) phosphorylation, leading to reduce the binding ability of STAT3 to the CD46 promoter, further attenuating CD46 transactivation. Activation of PKD by phorbol 12-myristate 13-acetate largely blocked the effect of EPA-mediated CD46 transactivation. Together, the current findings revealed a novel mechanism whereby EPA modulates CDC to inhibit the proliferation of cancer cells, broadening the pharmacological functions of EPA in anti-tumor therapy.
Peng et al. (Mon,) studied this question.