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从头合成脱氧核苷酸调节小细胞肺癌细胞生长和肿瘤进展。

De novo deoxyribonucleotide biosynthesis regulates cell growth and tumor progression in small-cell lung carcinoma.

机构信息

Shonai Regional Industry Promotion Center, Tsuruoka, Yamagata, 997-0052, Japan.

Tsuruoka Metabolomics Laboratory, National Cancer Center, Mizukami 246-2, Kakuganji, Tsuruoka, Yamagata, 997-0052, Japan.

出版信息

Sci Rep. 2021 Jun 29;11(1):13474. doi: 10.1038/s41598-021-92948-9.

DOI:10.1038/s41598-021-92948-9
PMID:34188151
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8242079/
Abstract

Deoxyribonucleotide biosynthesis from ribonucleotides supports the growth of active cancer cells by producing building blocks for DNA. Although ribonucleotide reductase (RNR) is known to catalyze the rate-limiting step of de novo deoxyribonucleotide triphosphate (dNTP) synthesis, the biological function of the RNR large subunit (RRM1) in small-cell lung carcinoma (SCLC) remains unclear. In this study, we established siRNA-transfected SCLC cell lines to investigate the anticancer effect of silencing RRM1 gene expression. We found that RRM1 is required for the full growth of SCLC cells both in vitro and in vivo. In particular, the deletion of RRM1 induced a DNA damage response in SCLC cells and decreased the number of cells with S phase cell cycle arrest. We also elucidated the overall changes in the metabolic profile of SCLC cells caused by RRM1 deletion. Together, our findings reveal a relationship between the deoxyribonucleotide biosynthesis axis and key metabolic changes in SCLC, which may indicate a possible link between tumor growth and the regulation of deoxyribonucleotide metabolism in SCLC.

摘要

从核糖核苷酸合成脱氧核苷酸为 DNA 的合成提供了构建模块，从而支持活性癌细胞的生长。虽然核糖核苷酸还原酶 (RNR) 已知可催化从头合成脱氧核糖核苷酸三磷酸 (dNTP) 的限速步骤，但 RNR 大亚基 (RRM1) 在小细胞肺癌 (SCLC) 中的生物学功能尚不清楚。在这项研究中，我们建立了 siRNA 转染的 SCLC 细胞系，以研究沉默 RRM1 基因表达对 SCLC 细胞的抗癌作用。我们发现 RRM1 是 SCLC 细胞在体外和体内完全生长所必需的。特别是，RRM1 的缺失诱导了 SCLC 细胞中的 DNA 损伤反应，并减少了 S 期细胞周期阻滞的细胞数量。我们还阐明了 RRM1 缺失引起的 SCLC 细胞代谢谱的整体变化。总之，我们的研究结果揭示了脱氧核苷酸生物合成轴与 SCLC 中关键代谢变化之间的关系，这可能表明肿瘤生长与 SCLC 中脱氧核苷酸代谢的调节之间存在可能的联系。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/8a02ed7f4748/41598_2021_92948_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/d4c443a1bd19/41598_2021_92948_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/5d22de33f88a/41598_2021_92948_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/b2bed7dac1ca/41598_2021_92948_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/162fc0d2e5ab/41598_2021_92948_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/2b4a746daf5b/41598_2021_92948_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/8a02ed7f4748/41598_2021_92948_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/d4c443a1bd19/41598_2021_92948_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/5d22de33f88a/41598_2021_92948_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/b2bed7dac1ca/41598_2021_92948_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/162fc0d2e5ab/41598_2021_92948_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/2b4a746daf5b/41598_2021_92948_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3287/8242079/8a02ed7f4748/41598_2021_92948_Fig6_HTML.jpg

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