An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis
An inducible pathway for degradation of FLIP protein sensitizes tumor cells to TRAIL-induced apoptosis
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DOI：
10.1074/jbc.m202458200
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发表时间：
2002-06-21
影响因子：
4.8
通讯作者：
Reed, JC
中科院分区：
文献类型：
--
作者：
Kim, Y;Suh, N;Reed, JC
TRAIL（Apo 2配体）是诱导细胞凋亡的细胞因子的肿瘤坏死因子（TNF）家族的成员。由于TRAIL优先杀死肿瘤细胞，而不伤害正常组织，因此人们对将这种生物因子应用于人类癌症治疗产生了兴趣。然而，并非所有肿瘤都对TRAIL有反应，这引发了关于耐药机制的问题。我们在这里证明，各种天然和合成的过氧化物酶体增殖物激活受体-γ（PPARgamma）的配体敏感的肿瘤，而不是正常细胞凋亡诱导的TRAIL。PPARgamma配体选择性地降低FLIP的水平，FLIP是一种凋亡抑制蛋白，其阻断TRAIL/TNF家族死亡受体信号传导中的早期事件。无论PPARgamma表达水平如何，甚至在存在PPARgamma显性负突变体的情况下，PPARgamma激动剂和拮抗剂都显示出这些作用，表明PPARgamma非依赖性机制。FLIP的减少和对TRAIL诱导的细胞凋亡的敏感性也与TNF-κ B无关，进一步表明了一种新的机制。PPARgamma调节剂诱导FLIP的泛素化和蛋白酶体依赖性降解，而不伴随FLIP mRNA的减少。这些发现表明，存在一种由PPAR γ调节的新型靶点，这种靶点控制FLIP蛋白质的周转，并提高了将PPARgamma调节剂与TRAIL结合以通过凋亡更有效地消除肿瘤细胞的可能性。
TRAIL (Apo2 ligand) is a member of the tumor necrosis factor (TNF) family of cytokines that induces apoptosis. Because TRAIL preferentially kills tumor cells, sparing normal tissues, interest has emerged in applying this biological factor for cancer therapy in humans. However, not all tumors respond to TRAIL, raising questions about resistance mechanisms. We demonstrate here that a variety of natural and synthetic ligands of peroxisome proliferator-activated receptor-gamma (PPARgamma) sensitize tumor but not normal cells to apoptosis induction by TRAIL. PPARgamma ligands selectively reduce levels of FLIP, an apoptosis-suppressing protein that blocks early events in TRAIL/TNF family death receptor signaling. Both PPARgamma agonists and antagonists displayed these effects, regardless of the levels of PPARgamma expression and even in the presence of a PPARgamma dominant-negative mutant, indicating a PPARgamma-independent mechanism. Reductions in FLIP and sensitization to TRAIL-induced apoptosis were also not correlated with TNF-kappaB, further suggesting a novel mechanism. PPARgamma modulators induced ubiquitination and proteasome-dependent degradation of FLIP, without concomitant reductions in FLIP mRNA. The findings suggest the existence of a pharmacologically regulated novel target of this class of drugs that controls FLIP protein turnover, and raise the possibility of combining PPARgamma modulators with TRAIL for more efficacious elimination of tumor cells through apoptosis.