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首页> 美国卫生研究院文献>Oncotarget >A combination of a ribonucleotide reductase inhibitor and histone deacetylase inhibitors downregulates EGFR and triggers BIM-dependent apoptosis in head and neck cancer
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A combination of a ribonucleotide reductase inhibitor and histone deacetylase inhibitors downregulates EGFR and triggers BIM-dependent apoptosis in head and neck cancer

机译：核糖核苷酸还原酶抑制剂和组蛋白脱乙酰基酶抑制剂的组合可下调EGFR并触发头颈癌的BIM依赖性细胞凋亡

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Head and neck squamous cell carcinomas (HNSCCs) are the sixth most common malignant neoplasm and more than 50% of patients succumb to this disease. HNSCCs are characterized by therapy resistance, which relies on the overexpression of anti-apoptotic proteins and on the aberrant regulation of the epidermal growth factor receptor (EGFR). As inherent and acquired resistance to therapy counteracts improvement of long-term survival, novel multi-targeting strategies triggering cancer cell death are urgently required. We investigated how induction of replicational stress by the ribonucleotide reductase inhibitor hydroxyurea (HU) combined with histone deacetylase inhibitors (HDACi) exerts anti-tumor activity. We treated HNSCC cell lines and freshly isolated tumor cells with HDACi, such as the clinically approved anti-epileptic drug valproic acid (VPA), in combination with HU. Our data demonstrate that at clinically achievable levels VPA/HU combinations efficiently block proliferation as well as clonogenic survival, and trigger apoptosis of HNSCC cells. In the presence of VPA/HU, such tumor cells increase expression of the pro-apoptotic BCL-2 family protein BIM, independent of wild-type p53 signaling and in the absence of increased expression of the p53 targets PUMA and BAX. The pro-apoptotic activity of BIM in HNSCCs was found critical for tumor cell death; ectopic overexpression of BIM induced HNSCC apoptosis and RNAi-mediated depletion of BIM protected HNSCC cells from VPA/HU. Also, significantly elevated BIM levels (p<0.01) were detectable in the apoptotic tumor centers versus proliferating tumor margins in HNSCC patients (n=31), underlining BIM's clinical relevance. Importantly, VPA/HU treatment additionally reduces expression and cell surface localization of EGFR. Accordingly, in a xenograft mouse model, VPA/HU efficiently blocked tumor growth (P<0.001) correlating with BIM induction and EGFR downregulation. We provide a molecular rationale for the potent anti-cancer activities of this drug combination. Our data suggest its exploitation as a potential strategy for the treatment of HNSCC and other tumor entities characterized by therapy resistance linked to dysregulated EGFR activation.
机译：头颈部鳞状细胞癌（HNSCC）是第六大最常见的恶性肿瘤，超过50％的患者死于该疾病。 HNSCCs的特征在于治疗耐药性，这取决于抗凋亡蛋白的过表达和表皮生长因子受体（EGFR）的异常调节。由于固有的和获得性的治疗抗性抵消了长期生存的改善，因此迫切需要触发癌细胞死亡的新颖的多靶点策略。我们调查了如何通过核糖核苷酸还原酶抑制剂羟基脲（HU）结合组蛋白脱乙酰基酶抑制剂（HDACi）诱导复制应激发挥抗肿瘤活性。我们用HDACi处理HNSCC细胞系和新鲜分离的肿瘤细胞，例如临床批准的抗癫痫药丙戊酸（VPA）与HU组合。我们的数据表明，在临床上可达到的水平上，VPA / HU组合有效地阻断了增殖以及克隆形成的存活，并触发了HNSCC细胞的凋亡。在存在VPA / HU的情况下，此类肿瘤细胞可独立于野生型p53信号传导增加凋亡前BCL-2家族蛋白BIM的表达，而在不增加p53表达的情况下会靶向PUMA和BAX。发现BIM在HNSCCs中的促凋亡活性对肿瘤细胞死亡至关重要。 BIM的异位过表达诱导HNSCC细胞凋亡，RNAi介导的BIM保护的HNSCC细胞从VPA / HU耗尽。同样，在HNSCC患者中，凋亡细胞中心的BIM水平显着升高（p <0.01），而肿瘤边缘的增殖却增高（n = 31），这说明了BIM的临床意义。重要的是，VPA / HU处理还可以降低EGFR的表达和细胞表面定位。因此，在异种移植小鼠模型中，VPA / HU有效地阻断了与BIM诱导和EGFR下调相关的肿瘤生长（P <0.001）。我们为这种药物组合的有效抗癌活性提供了分子基础。我们的数据表明，它被用作治疗HNSCC和其他肿瘤实体的潜在策略，其特征是与EGFR活化失调有关的治疗耐药性。

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