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. 2023 Aug 9;30(10):1414–1425. doi: 10.1038/s41417-023-00648-5

Fig. 6. The FOXO3a protein level is downregulated in cetuximab-resistant CRC cell lines.

Fig. 6

A KRASG13D mutation led to an increase in ERK phosphorylation and a decrease in FOXO3a protein levels in HCT116 and DLD-1 isogenic cells. B In RKO isogenic cells, the BRAFV600E mutation caused elevated phosphorylation of ERK and reduced FOXO3a protein levels. C The protein levels of FOXO3a, phosphorylated ERK, and total ERK were examined in Caco-2 cells and Caco-2-CR cells. D, E DLD-1(KRASG13D/-) cells were transfected with or without siRNAs targeting ERK1/2, then FOXO3a and ERK protein levels were analyzed (D). Cells were co-transfected with pFOXO3-TA-Luc and pRLK-TK plasmids to evaluate FOXO3a reporter activity (E). F–I FOXO3a and phosphorylated ERK protein levels were assessed in HT29 (BRAFV600E) cells (F) and Caco-2-CR cells (H) following treatment with U0126 (2 μM) for 4 h. FOXO3a reporter activity was examined in HT29 (BRAFV600E) cells (G) and Caco-2-CR cells (I) with or without U0126 treatment. J–L FOXO3a was overexpressed in DLD-1(KRASG13D/-) cells (J), and the activity of the FOXO3a reporter (K) and response to cetuximab (L) were evaluated in DLD-1(KRASG13D/-) cells with or without FOXO3a overexpression. M–O FOXO3a was overexpressed in HT29 (BRAFV600E) cells (M), and the activity of the FOXO3a reporter (N) and response to cetuximab (O) were evaluated in HT29 (BRAFV600E) cells with or without FOXO3a overexpression. P–R FOXO3a was overexpressed in Caco-2-CR cells (P), and the activity of the FOXO3a reporter (Q) and response to cetuximab (R) were evaluated in Caco-2-CR cells with or without FOXO3a overexpression. S Schematic diagrams illustrating how FOXO3a mediates 3-BP/cetuximab co-treatment-induced apoptosis and autophagy-dependent ferroptosis in cetuximab-resistant CRC cells.