Combined inhibition of RNA polymerase I and mTORC1/2 synergize to combat oral squamous cell carcinoma
Combined inhibition of RNA polymerase I and mTORC1/2 synergize to combat oral squamous cell carcinoma
复制标题
RNA 聚合酶 I 和 mTORC1/2 的联合抑制可协同对抗口腔鳞状细胞癌。
DOI：
10.1016/j.biopha.2020.110906
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发表时间：
2021-01-01
影响因子：
7.5
通讯作者：
Xu, Baoshan
中科院分区：
文献类型：
--
作者：
Shi, Shanwei;Luo, Huigen;Xu, Baoshan
口腔鳞状细胞癌（OSCC）是世界范围内头颈部癌症患者发病率和死亡率的主要原因。这种恶性疾病是具有挑战性的治疗，因为缺乏有效的治疗策略和高复发率。本研究旨在探讨针对核糖体生物发生和蛋白质翻译的单一和双重方法治疗与核糖体DNA（rDNA）拷贝数变异（CNV）相关的OSCC的有效性。在这里，我们发现，原发性OSCC肿瘤经常表现出45 S rDNA拷贝数的部分丢失，并表现出对CX 5461（RNA聚合酶I的选择性抑制剂）和CX 5461和INK 128（mTORC 1/2的有效抑制剂）的联合给药的高敏感性。联合处理显示出有希望的协同效应，诱导细胞凋亡和活性氧（ROS）的产生，并抑制细胞生长和增殖。此外，INK 128损害NHEJ-DNA修复途径以增强CX 5461的抗肿瘤活性。在体内，联合治疗协同抑制肿瘤生长，引发细胞凋亡，显着延长荷瘤小鼠的生存时间。此外，单独化合物治疗和联合给药似乎可以降低腹股沟淋巴结肿大的发生率。我们的研究支持CX 5461和INK 128的组合是一种新的有效的治疗策略，可以对抗这种癌症，并且45 S rDNA可以作为预测这种联合治疗的疗效的有用指标。
Oral squamous cell carcinoma (OSCC) is the major cause of morbidity and mortality in head and neck cancer patients worldwide. This malignant disease is challenging to treat because of the lack of effective curative strategies and the high incidence of recurrence. This study aimed to investigate the efficacy of a single and dual approach targeting ribosome biogenesis and protein translation to treat OSCC associated with the copy number variation (CNV) of ribosomal DNA (rDNA). Here, we found that primary OSCC tumors frequently exhibited a partial loss of 45S rDNA copy number and demonstrated a high susceptibility to CX5461 (a selective inhibitor of RNA polymerase I) and the coadministration of CX5461 and INK128 (a potent inhibitor of mTORC1/2). Combined treatment displayed the promising synergistic effects that induced cell apoptosis and reactive oxygen species (ROS) generation, and inhibited cell growth and proliferation. Moreover, INK128 compromised NHEJ-DNA repair pathway to reinforce the antitumor activity of CX5461. In vivo, the cotreatment synergistically suppressed tumor growth, triggered apoptosis and strikingly extended the survival time of tumor-bearing mice. Additionally, treatment with the individual compounds and coadministration appeared to reduce the incidence of enlarged inguinal lymph nodes. Our study supports that the combination of CX5461 and INK128 is a novel and efficacious therapeutic strategy that can combat this cancer and that 45S rDNA may serve as a useful indicator to predict the efficacy of this cotreatment.