Caspase-8 mutations associated with head and neck cancer differentially retain functional properties related to TRAIL-induced apoptosis and cytokine induction.
Caspase-8 mutations associated with head and neck cancer differentially retain functional properties related to TRAIL-induced apoptosis and cytokine induction.
复制标题
DOI：
10.1038/s41419-021-04066-z
复制
发表时间：
2021-08-06
影响因子：
9
通讯作者：
Johnson DE
中科院分区：
文献类型：
--
作者：
Cui Z;Dabas H;Leonard BC;Shiah JV;Grandis JR;Johnson DE
半胱氨酸蛋白酶caspase - 8在细胞受到肿瘤坏死因子相关凋亡诱导配体（TRAIL）等死亡配体刺激后会发生二聚化、加工和激活，并介导TRAIL对外源性凋亡途径的诱导。此外，caspase - 8通过一种不依赖其催化活性的机制介导TRAIL诱导的核因子κB（NF - κB）激活以及免疫抑制性趋化因子/细胞因子的上调。在10%的人类头颈部鳞状细胞癌（HNSCC）中，编码前体caspase - 8的基因发生突变。尽管缺乏实验证据，但HNSCC相关的caspase - 8突变通常被认为是功能丧失。为了研究它们的功能特性和表型效应，我们在细胞系模型中以强力霉素诱导的方式表达了18种与HNSCC相关的caspase - 8突变体，这些细胞系模型中的内源性野生型caspase - 8已被删除。我们观察到，氨基末端前结构域的8个突变体中有5个，但羧基末端催化区域的10个突变体中没有一个保留了介导TRAIL诱导的细胞凋亡的能力。前结构域发生突变的caspase - 8蛋白在二聚化方面存在缺陷，而所有10个催化区域突变体都能有效地二聚化，这表明突变蛋白的二聚化与细胞凋亡诱导之间呈反比关系。大约一半（8个中的3个）的前结构域突变体和10个中的9个催化区域突变体保留了介导TRAIL诱导免疫抑制性趋化因子CXCL1、白细胞介素 - 6（IL - 6）或白细胞介素 - 8（IL - 8）的能力。强力霉素诱导的野生型caspase - 8或一种代表性突变体的表达导致同基因HNSCC异种移植肿瘤中T细胞和自然杀伤T细胞（NKT细胞）的百分比增加。这些发现表明，与HNSCC相关的caspase - 8突变体保留了可能影响TRAIL介导的细胞凋亡和细胞因子诱导以及肿瘤微环境组成的特性。
The cysteine protease, caspase-8, undergoes dimerization, processing, and activation following stimulation of cells with death ligands such as TRAIL, and mediates TRAIL induction of the extrinsic apoptosis pathway. In addition, caspase-8 mediates TRAIL-induced activation of NF-κB and upregulation of immunosuppressive chemokines/cytokines, via a mechanism independent of caspase-8 catalytic activity. The gene encoding procaspase-8 is mutated in 10% of human head and neck squamous cell carcinomas (HNSCCs). Despite a paucity of experimental evidence, HNSCC-associated caspase-8 mutations are commonly assumed to be loss of function. To investigate their functional properties and phenotypic effects, 18 HNSCC-associated caspase-8 mutants were expressed in doxycycline-inducible fashion in cell line models wherein the endogenous wild-type caspase-8 was deleted. We observed that 5/8 mutants in the amino-terminal prodomain, but 0/10 mutants in the carboxyl-terminal catalytic region, retained an ability to mediate TRAIL-induced apoptosis. Caspase-8 proteins with mutations in the prodomain were defective in dimerization, whereas all ten of the catalytic region mutants efficiently dimerized, revealing an inverse relationship between dimerization and apoptosis induction for the mutant proteins. Roughly half (3/8) of the prodomain mutants and 9/10 of the catalytic region mutants retained the ability to mediate TRAIL induction of immunosuppressive CXCL1, IL-6, or IL-8. Doxycycline-induced expression of wild-type caspase-8 or a representative mutant led to an increased percentage of T and NKT cells in syngeneic HNSCC xenograft tumors. These findings demonstrate that HNSCC-associated caspase-8 mutants retain properties that may influence TRAIL-mediated apoptosis and cytokine induction, as well as the composition of the tumor microenvironment.
登录
查看更多内容
影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1158/1078-0432.ccr-14-0205
发表时间：
2014-06-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Onken MD;Winkler AE;Kanchi KL;Chalivendra V;Law JH;Rickert CG;Kallogjeri D;Judd NP;Dunn GP;Piccirillo JF;Lewis JS Jr;Mardis ER;Uppaluri R
通讯作者：
Uppaluri R
影响因子：
3.4
作者：
Judd, Nancy P.;Allen, Clint T.;Uppaluri, Ravindra
通讯作者：
Uppaluri, Ravindra
影响因子：
12.4
作者：
Schleich, K.;Buchbinder, J. H.;Lavrik, I. N.
通讯作者：
Lavrik, I. N.
影响因子：
12.4
作者：
Park, Hyun Ho
通讯作者：
Park, Hyun Ho