Targeting MUC1-C in combination with BTZ downregulates TIGAR and induces oxidative stress. (A) Schema of the MUC1-C subunit with the amino acid sequence of the MUC1-C cytoplasmic domain. Highlighted is the CQC motif that is necessary and sufficient for MUC1-C homodimerization and is the target of GO-203. GO-203 consists of a cell-penetrating poly-Arg sequence ([R]₉) upstream to CQCRRKN and binds to the MUC1-C cytoplasmic domain. CP-2 contains [R]₉ upstream to AQARRKN and is inactive in MUC1-C binding. (B-E) The indicated cells were left untreated (control; CTL) and treated with (1) 2.5 μM GO-203 alone each day for 72 hours, (2) 9 nM BTZ alone for 24 hours, or (3) GO-203 for 48 hours combined with BTZ for an additional 24 hours. GO-203/BTZ-treated cells were also incubated in the presence of 5 mM NAC for 72 hours. Lysates were immunoblotted with the indicated antibodies (B,E). Cells were analyzed for relative GSH levels (mean ± standard deviation [SD] of 3 determinations) (C) and relative hydrogen peroxide or superoxide levels (mean ± SD of 3 determinations) as compared with that obtained with control cells (D).