PMID- 33186350
OWN - NLM
STAT- MEDLINE
DCOM- 20210104
LR  - 20210104
IS  - 1545-7885 (Electronic)
IS  - 1544-9173 (Print)
IS  - 1544-9173 (Linking)
VI  - 18
IP  - 11
DP  - 2020 Nov
TI  - Nucleotide de novo synthesis increases breast cancer stemness and metastasis via 
      cGMP-PKG-MAPK signaling pathway.
PG  - e3000872
LID - 10.1371/journal.pbio.3000872 [doi]
LID - e3000872
AB  - 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.
FAU - Lv, Yajing
AU  - Lv Y
AUID- ORCID: 0000-0002-8253-3470
AD  - School of Medicine, Nankai University, Tianjin, China.
FAU - Wang, Xiaoshuang
AU  - Wang X
AD  - School of Medicine, Nankai University, Tianjin, China.
FAU - Li, Xiaoyu
AU  - Li X
AD  - School of Medicine, Nankai University, Tianjin, China.
FAU - Xu, Guangwei
AU  - Xu G
AD  - Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute 
      and Hospital, Tianjin, China.
FAU - Bai, Yuting
AU  - Bai Y
AD  - School of Medicine, Nankai University, Tianjin, China.
FAU - Wu, Jiayi
AU  - Wu J
AD  - School of Medicine, Nankai University, Tianjin, China.
FAU - Piao, Yongjun
AU  - Piao Y
AD  - School of Medicine, Nankai University, Tianjin, China.
FAU - Shi, Yi
AU  - Shi Y
AUID- ORCID: 0000-0003-2530-410X
AD  - School of Medicine, Nankai University, Tianjin, China.
FAU - Xiang, Rong
AU  - Xiang R
AUID- ORCID: 0000-0003-3487-7348
AD  - School of Medicine, Nankai University, Tianjin, China.
AD  - The International Collaborative Laboratory for Biological Medicine of the 
      Ministry of Education, Nankai University School of Medicine, Tianjin, China.
FAU - Wang, Longlong
AU  - Wang L
AUID- ORCID: 0000-0002-3932-1253
AD  - School of Medicine, Nankai University, Tianjin, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20201113
PL  - United States
TA  - PLoS Biol
JT  - PLoS biology
JID - 101183755
RN  - 0 (Nucleotides)
RN  - 0 (Purines)
RN  - EC 2.7.11.12 (Cyclic GMP-Dependent Protein Kinases)
RN  - EC 2.7.6.1 (Ribose-Phosphate Pyrophosphokinase)
RN  - H2D2X058MU (Cyclic GMP)
RN  - W60KTZ3IZY (purine)
SB  - IM
MH  - Adult
MH  - Animals
MH  - Breast Neoplasms/genetics/*metabolism
MH  - Cell Line, Tumor
MH  - China
MH  - Cyclic GMP/metabolism
MH  - Cyclic GMP-Dependent Protein Kinases/metabolism
MH  - Female
MH  - Gene Expression Profiling/methods
MH  - Humans
MH  - MAP Kinase Signaling System/physiology
MH  - Metabolomics/methods
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Neoplastic Stem Cells/*metabolism
MH  - Nucleotides/biosynthesis/*metabolism
MH  - Purines
MH  - Ribose-Phosphate Pyrophosphokinase/metabolism
MH  - Signal Transduction
PMC - PMC7688141
COIS- The authors have declared that no competing interests exist.
EDAT- 2020/11/14 06:00
MHDA- 2021/01/05 06:00
PMCR- 2020/11/13
CRDT- 2020/11/13 17:08
PHST- 2020/02/08 00:00 [received]
PHST- 2020/09/24 00:00 [accepted]
PHST- 2020/11/25 00:00 [revised]
PHST- 2020/11/14 06:00 [pubmed]
PHST- 2021/01/05 06:00 [medline]
PHST- 2020/11/13 17:08 [entrez]
PHST- 2020/11/13 00:00 [pmc-release]
AID - PBIOLOGY-D-20-00322 [pii]
AID - 10.1371/journal.pbio.3000872 [doi]
PST - epublish
SO  - PLoS Biol. 2020 Nov 13;18(11):e3000872. doi: 10.1371/journal.pbio.3000872. 
      eCollection 2020 Nov.