Erianin inhibits the growth and metastasis through autophagy-dependent ferroptosis in KRASG13D colorectal cancer

Abstract

Colorectal cancer (CRC) is the third most common cause of cancer mortality worldwide. Approximately 40% of CRC patients are KRAS sequence variation, including KRAS G13D mutation (KRAS^G13D) CRC patients, accounting for approximately 8% of all KRAS mutations in CRC patients and showing little benefit from anti-EGFR therapy. Therefore, there is an urgent need for new and effective anticancer agents in patients with KRAS^G13D CRC. Here, we identified a natural product, erianin, that directly interacted with purified recombinant human KRAS^G13D with a Kd of 1.1163 μM, which also significantly improve the thermal stability of KRAS^G13D. The cell viability assay showed that KRAS^G13D cells were more sensitive to erianin than KRAS^WT or KRAS^G12V cells. In vitro, results showed that erianin suppressed the migration, invasion and epithelial-mesenchymal transition (EMT) of KRAS^G13D CRC cells. Furthermore, erianin induced ferroptosis, as evidenced by the accumulation of Fe²⁺ and reactive oxygen species (ROS), lipid peroxidation, and changes in the mitochondrial morphology of KRAS^G13D CRC cells. Interestingly, we also found that erianin-induced ferroptosis was accompanied by autophagy. Moreover, the occurrence of erianin-induced ferroptosis is reversed by autophagy inhibitors (NH4Cl and Bafilomycin A1) and ATG5 knockdown, suggesting that erianin-induced ferroptosis is autophagy-dependent. In addition, we evaluated the inhibition of tumor growth and metastasis by erianin in vivo using a subcutaneous tumor model and a spleen-liver metastasis model, respectively. Collectively, these data provide novel insights into the anticancer activity of erianin, which is valuable for the further discussion and investigation of the use of erianin in clinical anticancer chemotherapy for KRAS^G13D CRC.

Keywords: Autophagy; Colorectal cancer; Erianin; Ferroptosis; KRAS(G13D); Metastasis.