Cancer cells that are resistant to Bax/Bak-dependent intrinsic apoptosis can be eliminated by proteasome inhibition. Here, we show that proteasome inhibition induces the formation of high molecular weight platforms in the cytosol that serve to activate caspase-8. The activation complexes contain Fas-associated death domain (FADD) and receptor-interacting serine/threonine-protein kinase 1 (RIPK1). Furthermore, the complexes contain TRAIL-receptor 2 (TRAIL-R2) but not TRAIL-receptor 1 (TRAIL-R1). While RIPK1 inhibition or depletion did not affect proteasome inhibitor-induced cell death, TRAIL-R2 was found essential for efficient caspase-8 activation, since the loss of TRAIL-R2 expression abrogated caspase processing, significantly reduced cell death, and promoted cell re-growth after drug washout. Overall, our study provides novel insight into the mechanisms by which proteasome inhibition eliminates otherwise apoptosis-resistant cells, and highlights the crucial role of a ligand-independent but TRAIL-R2-dependent activation mechanism for caspase-8 in this scenario.

通过蛋白酶体抑制可以消除对 Bax/Bak 依赖性内在细胞凋亡具有抗性的癌细胞。在这里，我们表明蛋白酶体抑制诱导细胞质中用于激活 caspase-8 的高分子量平台的形成。激活复合物包含 Fas 相关死亡结构域 (FADD) 和受体相互作用的丝氨酸/苏氨酸蛋白激酶 1 (RIPK1)。此外，复合物含有 TRAIL 受体 2 (TRAIL-R2) 但不含 TRAIL 受体 1 (TRAIL-R1)。虽然 RIPK1 抑制或消耗不影响蛋白酶体抑制剂诱导的细胞死亡，但发现 TRAIL-R2 对有效的 caspase-8 激活至关重要，因为 TRAIL-R2 表达的丧失消除了 caspase 加工，显着减少了细胞死亡，并促进了细胞再生。药物冲洗后的生长。总体，