Nucleotide de novo synthesis increases breast cancer stemness and metastasis via cGMP-PKG-MAPK signaling pathway.
Nucleotide de novo synthesis increases breast cancer stemness and metastasis via cGMP-PKG-MAPK signaling pathway.
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核苷酸从头合成通过 cGMP-PKG-MAPK 信号通路增加乳腺癌干性和转移
DOI：
10.1371/journal.pbio.3000872
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发表时间：
2020-11
期刊：
影响因子：
9.8
通讯作者：
Wang L
中科院分区：
文献类型：
--
作者：
Lv Y;Wang X;Li X;Xu G;Bai Y;Wu J;Piao Y;Shi Y;Xiang R;Wang L
近年来，通过代谢重编程来满足癌细胞的生物合成和生物能量需求引起了人们的极大兴趣。然而，代谢重编程在癌症转移中的作用尚未得到很好的阐明。在这里，我们筛选了小鼠中具有高度转移能力的乳腺癌细胞亚群，并通过分析代谢组和转录组来研究代谢改变，这在乳腺癌细胞，小鼠模型和患者组织中得到了证实。体外和体内进一步研究了核苷酸新生合成在肿瘤转移中的作用和机制。在我们的研究中，我们报道了作为转移性乳腺癌细胞关键代谢标志的核苷酸新生合成的增加，并揭示了强制核苷酸新生合成足以驱动乳腺癌细胞的转移。从头合成的关键代谢物鸟苷-5′-三磷酸（GTP）增加，能够产生更多的环鸟苷单磷酸（cGMP），激活cGMP依赖性蛋白激酶PKG和下游MAPK通路，导致肿瘤细胞干细胞性和转移增加。通过沉默磷酸核糖基焦磷酸合成酶2 （PRPS2）阻断新生合成可有效降低乳腺癌细胞的干性，减少肺转移。更有趣的是，在乳腺癌患者中，血浆尿酸（嘌呤的一种下游代谢物）的水平与患者的生存密切相关。我们的研究发现，增加de novo合成是转移性乳腺癌细胞的代谢标志，其代谢物可以调节信号通路，促进乳腺癌的发生和转移。众所周知，代谢重编程可以满足癌细胞的生物合成和生物能量需求，但在转移中的作用尚不清楚。这项研究表明，核苷酸代谢重编程导致cGMP-PKG-MAPK轴的增强，使乳腺癌细胞能够有效地在肺部定植和生长。
Metabolic reprogramming to fulfill the biosynthetic and bioenergetic demands of cancer cells has aroused great interest in recent years. However, metabolic reprogramming for cancer metastasis has not been well elucidated. Here, we screened a subpopulation of breast cancer cells with highly metastatic capacity to the lung in mice and investigated the metabolic alternations by analyzing the metabolome and the transcriptome, which were confirmed in breast cancer cells, mouse models, and patients’ tissues. The effects and the mechanisms of nucleotide de novo synthesis in cancer metastasis were further evaluated in vitro and in vivo. In our study, we report an increased nucleotide de novo synthesis as a key metabolic hallmark in metastatic breast cancer cells and revealed that enforced nucleotide de novo synthesis was enough to drive the metastasis of breast cancer cells. An increased key metabolite of de novo synthesis, guanosine-5'-triphosphate (GTP), is able to generate more cyclic guanosine monophosphate (cGMP) to activate cGMP-dependent protein kinases PKG and downstream MAPK pathway, resulting in the increased tumor cell stemness and metastasis. Blocking de novo synthesis by silencing phosphoribosylpyrophosphate synthetase 2 (PRPS2) can effectively decrease the stemness of breast cancer cells and reduce the lung metastasis. More interestingly, in breast cancer patients, the level of plasma uric acid (UA), a downstream metabolite of purine, is tightly correlated with patient’s survival. Our study uncovered that increased de novo synthesis is a metabolic hallmark of metastatic breast cancer cells and its metabolites can regulate the signaling pathway to promote the stemness and metastasis of breast cancer. Metabolic reprogramming to fulfil the biosynthetic and bioenergetic demands of cancer cells is well known, but a role in metastasis is less clear. This study shows that nucleotide metabolic reprogramming leads to an enhancement of the cGMP-PKG-MAPK axis, enabling breast cancer cells to effectively colonize and grow in the lung.
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影响因子：
82.9
作者：
通讯作者：
--
DOI：
10.1073/pnas.78.11.6858
发表时间：
1981-01-01
期刊：
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES
影响因子：
--
作者：
AMES, BN;CATHCART, R;HOCHSTEIN, P
通讯作者：
HOCHSTEIN, P
DOI：
10.1126/science.aac6054
发表时间：
2016-02-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
French JB;Jones SA;Deng H;Pedley AM;Kim D;Chan CY;Hu H;Pugh RJ;Zhao H;Zhang Y;Huang TJ;Fang Y;Zhuang X;Benkovic SJ
通讯作者：
Benkovic SJ
影响因子：
64.5
作者：
Guo, Dagang;Tan, Ying-cai;Huang, Xin-Yun
通讯作者：
Huang, Xin-Yun
影响因子：
64.8
作者：
Obradovic, Milan M. S.;Hamelin, Baptiste;Bentires-Alj, Mohamed
通讯作者：
Bentires-Alj, Mohamed