Fig. 4. Mathematical modelling predicts lowering the MOMP threshold as a superior strategy to sensitize non-responder cell lines to TRAIL/TL32711.

a Basal expression level of procaspase-8 and Bid proteins analysed from whole-cell lysates by western blotting. Actin served as loading control. b Protein amounts were quantified from original 12 bit grey scale images and compared between responder and non-responder cell lines. Lines represent medians. (* significant, Mann–Whitney U-test) c Topology of the mathematical model shown in systems biology graphical notation. Degradation processes were implemented but omitted here for clarity. Active caspase-8 served to trigger signaling. d Calculated tBid profiles for conditions of responder and non-responder cell lines. Taking estimates for cell-to-cell differences in protein expression amounts in account, n = 200 simulations were performed per cell line. e Predictions on the impact of enhanced caspase-8 activation on cell death in MZ304 cells. f Predictions on the impact of lowering the MOMP threshold in MZ304 cells. Bar graphs in e, f show means ± s.d., assuming 10% cell-to-cell heterogeneity in the efficacy of the sensitization strategy