The novel proteasome inhibitor carfilzomib activates and enhances extrinsic apoptosis involving stabilization of death receptor 5.
The novel proteasome inhibitor carfilzomib activates and enhances extrinsic apoptosis involving stabilization of death receptor 5.
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DOI：
10.18632/oncotarget.3947
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发表时间：
2015-07-10
期刊：
影响因子：
--
通讯作者：
Sun SY
中科院分区：
文献类型：
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作者：
Han B;Yao W;Oh YT;Tong JS;Li S;Deng J;Yue P;Khuri FR;Sun SY
卡菲佐米(CFZ)是第二代蛋白酶体抑制剂，被批准用于治疗多发性骨髓瘤。它能诱导人类癌细胞的凋亡，但其潜在的机制尚不清楚。在目前的研究中，我们发现CFZ降低了几种人类癌细胞的存活率，并诱导了细胞的凋亡。由于FADD缺乏保护癌细胞不发生凋亡，CFZ至少部分地由于激活了外在的凋亡途径而诱导细胞凋亡。CFZ增加了不同癌细胞系中DR5的总水平和细胞表面水平，从而增强了TRAIL诱导的细胞凋亡。DR5缺乏对CFZ单独或与TRAIL合用诱导癌细胞凋亡有保护作用。这些数据表明，DR5的上调是CFZ诱导的细胞凋亡和TRAIL诱导的细胞凋亡的关键机制。CFZ抑制DR5的降解，提示DR5的稳定作用有助于CFZ诱导的DR5表达上调。综上所述，本研究强调了DR5上调在CFZ诱导人癌细胞凋亡和增强TRAIL诱导人癌细胞凋亡中的重要作用。
Carfilzomib (CFZ) is a second generation proteasome inhibitor approved for the treatment of patients with multiple myeloma. It induces apoptosis in human cancer cells; but the underlying mechanisms remain undefined. In the present study, we show that CFZ decreases the survival of several human cancer cell lines and induces apoptosis. Induction of apoptosis by CFZ occurs, at least in part, due to activation of the extrinsic apoptotic pathway, since FADD deficiency protected cancer cells from undergoing apoptosis. CFZ increased total and cell surface levels of DR5 in different cancer cell lines; accordingly it enhanced TRAIL-induced apoptosis. DR5 deficiency protected cancer cells from induction of apoptosis by CFZ either alone or in combination with TRAIL. These data together convincingly demonstrate that DR5 upregulation is a critical mechanism accounting for CFZ-induced apoptosis and enhancement of TRAIL-induced apoptosis. CFZ inhibited the degradation of DR5, suggesting that DR5 stabilization contributes to CFZ-induced DR5 upregulation. In summary, the present study highlights the important role of DR5 upregulation in CFZ-induced apoptosis and enhancement of TRAIL-induced apoptosis in human cancer cells.