Fig. 7

Mechanism of cisplatin MLN4924 combination action in MPM cells. MLN4924-non-responsive cells escape the lethal UPR because the low levels of UBE2M and SKP2, and the high activity of proteasome even in the presence of cisplatin prevents the accumulation of unfolded proteins and the consequent immunogenic cell death (ICD). By contrast, MLN4924-responsive cells had higher SKP2 levels and UBE2M activity, coupled with low proteasome activity when treated with cisplatin. The simultaneous block of SCF complex and proteasome enormously increases the accumulation of unfolded/ubiquitinated protein, triggering ER stress, exposure of calreticulin (CRT) on the cell surface, release of ATP and high mobile group B1 (HMGB1), activation of dendritic cells (DC) and CD8⁺T-cell against tumor, therefore inducing a canonical ICD. N: NEDD8.