Neuro-Oncology Branch, National Cancer Institute, Center for Cancer Research, National Institutes of Health, Building 35 Room 2B203 35 Convent Dr., Bethesda, MD, 20892, USA.
CAMS Key Laboratory of Synthetic Biology for Drug Innovation, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking, 100050, China.
J Exp Clin Cancer Res. 2022 Apr 6;41(1):126. doi: 10.1186/s13046-022-02350-0.
Compared to normal cells, cancer cells exhibit a higher level of oxidative stress, which primes key cellular and metabolic pathways and thereby increases their resilience under oxidative stress. This higher level of oxidative stress also can be exploited to kill tumor cells while leaving normal cells intact. In this study we have found that isovalerylspiramycin I (ISP I), a novel macrolide antibiotic, suppresses cancer cell growth and tumor metastases by targeting the nucleolar protein selenoprotein H (SELH), which plays critical roles in keeping redox homeostasis and genome stability in cancer cells.
We developed ISP I through genetic recombination and tested the antitumor effects using primary and metastatic cancer models. The drug target was identified using the drug affinity responsive target stability (DARTS) and mass spectrum assays. The effects of ISP I were assessed for reactive oxygen species (ROS) generation, DNA damage, R-loop formation and its impact on the JNK2/TIF-IA/RNA polymerase I (POLI) transcription pathway.
ISP I suppresses cancer cell growth and tumor metastases by targeting SELH. Suppression of SELH induces accumulation of ROS and cancer cell-specific genomic instability. The accumulation of ROS in the nucleolus triggers nucleolar stress and blocks ribosomal RNA transcription via the JNK2/TIF-IA/POLI pathway, causing cell cycle arrest and apoptosis in cancer cells.
We demonstrated that ISP I links cancer cell vulnerability to oxidative stress and RNA biogenesis by targeting SELH. This suggests a potential new cancer treatment paradigm, in which the primary therapeutic agent has minimal side-effects and hence may be useful for long-term cancer chemoprevention.
与正常细胞相比，癌细胞表现出更高水平的氧化应激，这激活了关键的细胞和代谢途径，从而提高了它们在氧化应激下的韧性。这种更高水平的氧化应激也可以被利用来杀死肿瘤细胞，同时使正常细胞保持完整。在这项研究中，我们发现一种新型大环内酯抗生素异戊酰螺旋霉素 I（ISP I）通过靶向核仁蛋白硒蛋白 H（SELH）抑制癌细胞生长和肿瘤转移，SELH 在维持癌细胞氧化还原平衡和基因组稳定性方面发挥着关键作用。
我们通过基因重组开发了 ISP I，并使用原发性和转移性癌症模型测试了其抗肿瘤效果。使用药物亲和反应靶标稳定性（DARTS）和质谱分析确定了药物靶标。评估了 ISP I 对活性氧（ROS）生成、DNA 损伤、R 环形成及其对 JNK2/TIF-IA/RNA 聚合酶 I（POLI）转录途径的影响。
ISP I 通过靶向 SELH 抑制癌细胞生长和肿瘤转移。SELH 的抑制导致 ROS 的积累和癌细胞特异性基因组不稳定性。ROS 在核仁中的积累引发核仁应激，并通过 JNK2/TIF-IA/POLI 途径阻断核糖体 RNA 转录，导致癌细胞周期停滞和凋亡。
我们证明 ISP I 通过靶向 SELH 将癌细胞对氧化应激和 RNA 生物发生的易感性联系起来。这表明了一种潜在的新癌症治疗范例，其中主要治疗剂副作用极小，因此可能对长期癌症化学预防有用。
