FBXO31 sensitizes cancer stem cells‐like cells to cisplatin by promoting ferroptosis and facilitating proteasomal degradation of GPX4 in cholangiocarcinoma

Abstract

BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a malignant tumour originating from the biliary epithelium that easily infiltrates, metastasizes and recurs. The deficiency of FBXO31 facilitates the initiation and progression of several types of cancer. However, the involvement of FBXO31 in CCA progression has remained unclear. METHODS: qRT-PCR was used to detect the expression of FBXO31 in CCA. The biological functions of FBXO31 were confirmed in vivo and in vitro. Sphere formation and flow cytometry were used to identify the stem cell properties of CCA. RESULTS: FBXO31 is downregulated in CCA and that deficiency of FBXO31 is associated with the TNM stage of CCA. Functional studies showed FBXO31 inhibits cell growth, migration, invasion, cancer stem cell (CSC) properties and epithelial-mesenchymal transition (EMT) in vitro and impedes tumour growth in vivo. In addition, overexpression of FBXO31 increases the cisplatin (CDDP) sensitivity of CCA cells. RNA-sequencing analysis revealed that FBXO31 is involved in redox biology and metal ion metabolism in CCA cells during CDDP treatment. Further studies revealed that FBXO31 enhances ferroptosis induced by CDDP in CCA and CSC-like cells. FBXO31 enhances ubiquitination of glutathione peroxidase 4 (GPX4), which leads to proteasomal degradation of GPX4. Moreover, overexpression of GPX4 compromises the promoting effects of FBXO31 on CDDP-induced ferroptosis in CCA and CSC-like cells. CONCLUSIONS: Our studies indicate that FBXO31 functions as a tumour suppressor in CCA and sensitizes CSC-like cells to CDDP by promoting ferroptosis and facilitating the proteasomal degradation of GPX4.