Raulf N, El-Attar R, Kulms D, Lecis D, Delia D, Walczak H, Papenfuss K, Odell E, Tavassoli M
Department of Molecular Oncology, King's College London, Guy's Hospital Campus, Hodgkin Building, London SE1 1UL, UK.
Experimental Dermatology, Department of Dermatology, TU-Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.
Br J Cancer. 2014 Nov 11;111(10):1955-64. doi: 10.1038/bjc.2014.521. Epub 2014 Oct 14.
Current treatment strategies for head and neck cancer are associated with significant morbidity and up to 50% of patients relapse, highlighting the need for more specific and effective therapeutics. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) and Smac mimetics (SMs) are promising anticancer agents, but their effect on head and neck squamous cell carcinoma (HNSCC) remains unknown.
We examined the response of a panel of nine HNSCC cell lines to TRAIL and SMs and investigated the mechanism of cell type-specific response by functional analysis.
Head and neck cancer cell lines revealed a converse response pattern with three cell lines being highly sensitive to Smac-164 (SM) but resistant to TRAIL, whereas the other six were sensitive to TRAIL but resistant to SM. Distinct protein expression and activation patterns were found to be associated with susceptibility of HNSCC cell lines to TRAIL and SM. Tumour necrosis factor-related apoptosis-inducing ligand sensitivity was associated with high caspase-8 and Bid protein levels, and TRAIL-sensitive cell lines were killed via the type II extrinsic apoptotic pathway. Smac mimetic-sensitive cells expressed low levels of caspase-8 and Bid but had high TNF-α expression. Smac mimetic-induced cell death was associated with caspase-10 activation, suggesting that in the absence of caspase-8, caspase-10 mediates response to SM. Cotreatment with TNF-α sensitised the resistant cells to SM, demonstrating a decisive role for TNF-α-driven feedback loop in SM sensitivity.
Tumour necrosis factor-related apoptosis-inducing ligand and SMs effectively kill HNSCC cell lines and therefore represent potential targeted therapeutics for head and neck cancer. Distinct molecular mechanisms determine the sensitivity to each agent, with levels of TNF-α, caspase-8, Bid and caspase-10 providing important predictive biomarkers of response to these agents.
目前头颈部癌的治疗策略会导致严重的发病率，且高达50%的患者会复发，这凸显了对更具特异性和有效性的治疗方法的需求。肿瘤坏死因子相关凋亡诱导配体（TRAIL）和Smac模拟物（SMs）是很有前景的抗癌药物，但它们对头颈部鳞状细胞癌（HNSCC）的作用仍不清楚。
我们检测了一组9种HNSCC细胞系对TRAIL和SMs的反应，并通过功能分析研究了细胞类型特异性反应的机制。
头颈部癌细胞系呈现出相反的反应模式，三种细胞系对Smac-164（SM）高度敏感但对TRAIL耐药，而其他六种对TRAIL敏感但对SM耐药。发现不同的蛋白质表达和激活模式与HNSCC细胞系对TRAIL和SM的敏感性相关。肿瘤坏死因子相关凋亡诱导配体敏感性与高半胱天冬酶-8和Bid蛋白水平相关，对TRAIL敏感的细胞系通过II型外源性凋亡途径被杀死。对Smac模拟物敏感的细胞表达低水平的半胱天冬酶-8和Bid，但具有高肿瘤坏死因子-α表达。Smac模拟物诱导的细胞死亡与半胱天冬酶-10激活相关，表明在缺乏半胱天冬酶-8的情况下，半胱天冬酶-10介导对SM的反应。与肿瘤坏死因子-α联合治疗使耐药细胞对SM敏感，证明肿瘤坏死因子-α驱动的反馈环在SM敏感性中起决定性作用。
肿瘤坏死因子相关凋亡诱导配体和SMs可有效杀死HNSCC细胞系，因此代表了头颈部癌潜在的靶向治疗方法。不同的分子机制决定了对每种药物的敏感性，肿瘤坏死因子-α、半胱天冬酶-8、Bid和半胱天冬酶-10的水平提供了对这些药物反应的重要预测生物标志物。
