Erianin Inhibits Colorectal Cancer Cell Malignant Progression by Inducing Cuproptosis

Abstract

Background: Cuproptosis, a recently reported novel form of cell death that is dependent on abnormal Cu (II) accumulation, has been reported to be mediated by the ferredoxin 1 (FDX1) and lipoylation of dihydrolipoamide S-acetyltransferase (DLAT) and dihydrolipoamide S-succinyltransferase (DLST) proteins. Erianin is extracted from traditional herbs and reported as a potential anti-tumor agent. In this study, we aimed to delve to whether erianin induces cuproptosis of colorectal cancer (CRC) cells and to explore the underlying mechanisms. Methods: CRC cells were treated with the cuproptosis inducer elesclomol (Ele) and erianin (ERA). Then cell proliferation was measured with a cell counting kit 8 (CCK-8) assay and colony formation. The in vivo growth of CRC cells was measured by a xenograft tumor model. The intracellular levels of Cu, pyruvate acid (PA), and α-ketoglutarate dehydrogenase (α-KG) were measured to determine the relationship between cuproptosis and the tricarboxylic acid (TCA) cycle. The lipoylated proteins levels were measured by western blot. The oligomerization of the proteins was observed using immunofluorescence. Knockdown of FDX1 was conducted using siRNA and then cell growth and cuproptosis were measured. Results: Elesclomol suppressed CRC cell growth in vitro and in vivo, induced accumulation of Cu and decreased the production of PA and α-KG, suggesting the induction of cuproptosis. Administration of erianin enhanced the anti-tumor effects of elesclomol. Erianin treatment increased the expression of FDX1 and induced the lipoylation of DLAT and DLST protein, whereas depletion of FDX1 suppressed the erianin-induced CRC cell cuproptosis and protein lipoylation. Conclusions: Erianin induced cuproptosis of CRC cells to suppress CRC cell growth. Erianin may increase FDX1 expression and protein lipoylation to induce ferroptosis.