PMID- 32296044
OWN - NLM
STAT- MEDLINE
DCOM- 20211007
LR  - 20211110
IS  - 2059-3635 (Electronic)
IS  - 2095-9907 (Print)
IS  - 2059-3635 (Linking)
VI  - 5
IP  - 1
DP  - 2020 Feb 21
TI  - Both IDO1 and TDO contribute to the malignancy of gliomas via the Kyn-AhR-AQP4 
      signaling pathway.
PG  - 10
LID - 10.1038/s41392-019-0103-4 [doi]
LID - 10
AB  - Indoleamine 2,3-dioxygenase 1 (IDO1), indoleamine 2,3-dioxygenase 2 (IDO2), and 
      tryptophan 2,3-dioxygenase (TDO) initiate the first step of the kynurenine 
      pathway (KP), leading to the transformation of L-tryptophan (Trp) into 
      L-kynurenine (Kyn) and other downstream metabolites. Kyn is known as an 
      endogenous ligand of the aryl hydrocarbon receptor (AhR). Activation of AhR 
      through TDO-derived Kyn is a novel mechanism to support tumor growth in gliomas. 
      However, the role of IDO1 and IDO2 in this mechanism is still unknown. Herein, by 
      using clinical samples, we found that the expression and activity of IDO1 and/or 
      TDO (IDO1/TDO) rather than IDO2 were positively correlated with the pathologic 
      grades of gliomas. The expression of IDO1/TDO rather than IDO2 was positively 
      correlated with the Ki67 index and overall survival. The expression of IDO1/TDO 
      was positively correlated with the expression of aquaporin 4 (AQP4), implying the 
      potential involvement of IDO1/TDO in glioma cell motility. Mechanistically, we 
      found that IDO1/TDO accounted for the release of Kyn, which activated AhR to 
      promote cell motility via the Kyn-AhR-AQP4 signaling pathway in U87MG glioma 
      cells. RY103, an IDO1/TDO dual inhibitor, could block the IDO1/TDO-Kyn-AhR-AQP4 
      signaling pathway and exert anti-glioma effects in GL261 orthotopic glioma mice. 
      Together, our results showed that the IDO1/TDO-Kyn-AhR-AQP4 signaling pathway is 
      a new mechanism underlying the malignancy of gliomas, and suggest that both IDO1 
      and TDO might be valuable therapeutic targets for gliomas.
FAU - Du, Lisha
AU  - Du L
AD  - State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan 
      University, Songhu Road 2005, Shanghai, 200438, China.
FAU - Xing, Zikang
AU  - Xing Z
AD  - State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan 
      University, Songhu Road 2005, Shanghai, 200438, China.
FAU - Tao, Bangbao
AU  - Tao B
AD  - Department of Neurosurgery, Xinhua Hospital, Shanghai Jiaotong University, School 
      of Medicine, Kongjiang Road 1665, Shanghai, 200092, China.
FAU - Li, Tianqi
AU  - Li T
AD  - State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan 
      University, Songhu Road 2005, Shanghai, 200438, China.
FAU - Yang, Dan
AU  - Yang D
AD  - State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan 
      University, Songhu Road 2005, Shanghai, 200438, China.
FAU - Li, Weirui
AU  - Li W
AD  - State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan 
      University, Songhu Road 2005, Shanghai, 200438, China.
FAU - Zheng, Yuanting
AU  - Zheng Y
AD  - State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan 
      University, Songhu Road 2005, Shanghai, 200438, China.
FAU - Kuang, Chunxiang
AU  - Kuang C
AD  - Department of Chemistry, Tongji University, Siping Road 1239, Shanghai, 200092, 
      China.
FAU - Yang, Qing
AU  - Yang Q
AD  - State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan 
      University, Songhu Road 2005, Shanghai, 200438, China. yangqing68@fudan.edu.cn.
AD  - Institute of Science and Technology for Brain-Inspired Intelligence, Fudan 
      University, Handan Road 220, Shanghai, 200433, China. yangqing68@fudan.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200221
PL  - England
TA  - Signal Transduct Target Ther
JT  - Signal transduction and targeted therapy
JID - 101676423
RN  - 0 (AQP4 protein, human)
RN  - 0 (Aquaporin 4)
RN  - 0 (IDO1 protein, human)
RN  - 0 (Indoleamine-Pyrrole 2,3,-Dioxygenase)
RN  - 0 (Ki-67 Antigen)
RN  - 0 (MKI67 protein, human)
RN  - 0 (Receptors, Aryl Hydrocarbon)
RN  - 343-65-7 (Kynurenine)
RN  - EC 1.13.11.11 (Tryptophan Oxygenase)
EIN - Signal Transduct Target Ther. 2021 Nov 8;6(1):385. PMID: 34750349
MH  - Animals
MH  - Aquaporin 4/*genetics
MH  - Carcinogenesis/*genetics
MH  - Female
MH  - Glioma/*genetics/pathology
MH  - Humans
MH  - Indoleamine-Pyrrole 2,3,-Dioxygenase/*genetics
MH  - Ki-67 Antigen/genetics
MH  - Kynurenine/genetics
MH  - Male
MH  - Mice
MH  - Middle Aged
MH  - Receptors, Aryl Hydrocarbon/genetics
MH  - Signal Transduction/genetics
MH  - Tryptophan Oxygenase/*genetics
PMC - PMC7033114
COIS- The authors declare no competing interests.
EDAT- 2020/04/17 06:00
MHDA- 2021/10/08 06:00
PMCR- 2020/02/21
CRDT- 2020/04/17 06:00
PHST- 2019/08/03 00:00 [received]
PHST- 2019/11/27 00:00 [accepted]
PHST- 2019/11/25 00:00 [revised]
PHST- 2020/04/17 06:00 [entrez]
PHST- 2020/04/17 06:00 [pubmed]
PHST- 2021/10/08 06:00 [medline]
PHST- 2020/02/21 00:00 [pmc-release]
AID - 10.1038/s41392-019-0103-4 [pii]
AID - 103 [pii]
AID - 10.1038/s41392-019-0103-4 [doi]
PST - epublish
SO  - Signal Transduct Target Ther. 2020 Feb 21;5(1):10. doi: 
      10.1038/s41392-019-0103-4.