Curcumol promotes ferroptosis of colon cancer by targeting the ubiquitination and degradation of GPX4

Abstract

Background and aim: Colon cancer (CC) is one of the common malignant tumors in the digestive tract, the prognosis of CC patients has never been satisfying. A Ferrous-dependent form that regulates cell death, plays a key role in cancer development. As a core regulator of ferroptosis, GPX4 has become a potential molecular target for the development of antitumor drugs. Curcumol (Cur), a sesquiterpene natural product, it has significant anti-tumor effect. However, whether Cur mediates ferroptosis in colon cancer and its mechanism are still unclear. This study aimed to investigate the underlying mechanisms of Cur anti-tumor. Experimental procedure: By investigating the Cancer Genome Atlas (TCGA) database and tissue immunofluorescence staining was also used to detect the levels of GPX4 protein in CC and matching paracancerous tissues. The anti-CC and pro-ferroptosis effects of Cur were detected in the vivo and vitro experiment. The interaction between Cur and GPX4 was predicted. In addition, the potential mechanism of Cur anti-CC was further discussed. Co-immunoprecipitation was used to confirm Cur-mediated GPX4 ubiquitination. Results and conclusion: GPX4 was upregulated in CC tissue and was correlated with poor survival of patients. Cur inhibited the proliferation of CC cells, accompanied by regulating Fe2+ overload, reactive oxygen species (ROS) formation, malondialdehyde (MDA) production and superoxide dismutase (SOD) consumption. Furthermore, GPX4 was predicted and verified as the direct target of Cur by molecular docking and structure-based virtual prediction. Meanwhile, Cur could promote the ubiquitination-mediated degradation of GPX4, induce ferroptosis in CC cells and regulate the expression of ferroptosis-related protein FTH1 and TfR1. In addition, when GPX4 was overexpressed (GPX4-OE), the inhibitory effect of Cur on the expression of GPX4 and ferroptosis-related protein FTH1 and the promotion of TfR1 expression were abolished. Cur could inhibit CC by increasing the ubiquitination degradation level of GPX4 to induce ferroptosis in CC cells.

Keywords

• Colon cancer
• Curcumol
• GPX4
• Ferroptosis
• Ubiquitination