PMID- 29867114
OWN - NLM
STAT- MEDLINE
DCOM- 20191203
LR  - 20211204
IS  - 2041-4889 (Electronic)
VI  - 9
IP  - 6
DP  - 2018 Jun 4
TI  - Sorting nexin 10 controls mTOR activation through regulating amino-acid 
      metabolism in colorectal cancer.
PG  - 666
LID - 10.1038/s41419-018-0719-2 [doi]
LID - 666
AB  - Amino-acid metabolism plays a vital role in mammalian target of rapamycin (mTOR) 
      signaling, which is the pivot in colorectal cancer (CRC). Upregulated 
      chaperone-mediated autophagy (CMA) activity contributes to the regulation of 
      metabolism in cancer cells. Previously, we found that sorting nexin 10 (SNX10) is 
      a critical regulator in CMA activation. Here we investigated the role of SNX10 in 
      regulating amino-acid metabolism and mTOR signaling pathway activation, as well 
      as the impact on the tumor progression of mouse CRC. Our results showed that 
      SNX10 deficiency promoted colorectal tumorigenesis in male FVB mice and CRC cell 
      proliferation and survival. Metabolic pathway analysis of gas chromatography-mass 
      spectrometry (GC-MS) data revealed unique changes of amino-acid metabolism by 
      SNX10 deficiency. In HCT116 cells, SNX10 knockout resulted in the increase of CMA 
      and mTOR activation, which could be abolished by chloroquine treatment or 
      reversed by SNX10 overexpression. By small RNA interference (siRNA), we found 
      that the activation of mTOR was dependent on lysosomal-associated membrane 
      protein type-2A (LAMP-2A), which is a limiting factor of CMA. Similar results 
      were also found in Caco-2 and SW480 cells. Ultra-high-performance liquid 
      chromatography-quadrupole time of flight (UHPLC-QTOF) and GC-MS-based untargeted 
      metabolomics revealed that 10 amino-acid metabolism in SNX10-deficient cells were 
      significantly upregulated, which could be restored by LAMP-2A siRNA. All of these 
      amino acids were previously reported to be involved in mTOR activation. In 
      conclusion, this work revealed that SNX10 controls mTOR activation through 
      regulating CMA-dependent amino-acid metabolism, which provides potential target 
      and strategy for treating CRC.
FAU - Le, Yunchen
AU  - Le Y
AD  - School of Pharmacy, Fudan University, Shanghai, 201203, PR China.
FAU - Zhang, Sulin
AU  - Zhang S
AD  - School of Pharmacy, Fudan University, Shanghai, 201203, PR China.
FAU - Ni, Jiahui
AU  - Ni J
AD  - School of Pharmacy, Fudan University, Shanghai, 201203, PR China.
FAU - You, Yan
AU  - You Y
AD  - School of Pharmacy, Fudan University, Shanghai, 201203, PR China.
FAU - Luo, Kejing
AU  - Luo K
AD  - School of Pharmacy, Fudan University, Shanghai, 201203, PR China.
FAU - Yu, Yunqiu
AU  - Yu Y
AD  - School of Pharmacy, Fudan University, Shanghai, 201203, PR China. 
      yqyu@shmu.edu.cn.
FAU - Shen, Xiaoyan
AU  - Shen X
AD  - School of Pharmacy, Fudan University, Shanghai, 201203, PR China. 
      shxiaoy@fudan.edu.cn.
LA  - eng
GR  - 81773744/National Natural Science Foundation of China (National Science 
      Foundation of China)/International
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180604
PL  - England
TA  - Cell Death Dis
JT  - Cell death & disease
JID - 101524092
RN  - 0 (Amino Acids)
RN  - 0 (Lysosomal-Associated Membrane Protein 2)
RN  - 0 (Molecular Chaperones)
RN  - 0 (Nucleotides)
RN  - 0 (SNX10 protein, human)
RN  - 0 (SNX10 protein, mouse)
RN  - 0 (Sorting Nexins)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
SB  - IM
MH  - Amino Acids/*metabolism
MH  - Animals
MH  - Autophagy
MH  - Caco-2 Cells
MH  - Carcinogenesis/metabolism/pathology
MH  - Cell Proliferation
MH  - Cell Survival
MH  - Colorectal Neoplasms/*metabolism/pathology
MH  - HCT116 Cells
MH  - Humans
MH  - Lysosomal-Associated Membrane Protein 2/metabolism
MH  - Male
MH  - Metabolomics
MH  - Mice, Knockout
MH  - Models, Biological
MH  - Molecular Chaperones/metabolism
MH  - Multivariate Analysis
MH  - Nucleotides/metabolism
MH  - Signal Transduction
MH  - Sorting Nexins/deficiency/*metabolism
MH  - TOR Serine-Threonine Kinases/*metabolism
MH  - Up-Regulation
PMC - PMC5986761
COIS- The authors declare that they have no conflict of interest.
EDAT- 2018/06/06 06:00
MHDA- 2019/12/04 06:00
PMCR- 2018/06/04
CRDT- 2018/06/06 06:00
PHST- 2018/01/26 00:00 [received]
PHST- 2018/05/17 00:00 [accepted]
PHST- 2018/05/16 00:00 [revised]
PHST- 2018/06/06 06:00 [entrez]
PHST- 2018/06/06 06:00 [pubmed]
PHST- 2019/12/04 06:00 [medline]
PHST- 2018/06/04 00:00 [pmc-release]
AID - 10.1038/s41419-018-0719-2 [pii]
AID - 719 [pii]
AID - 10.1038/s41419-018-0719-2 [doi]
PST - epublish
SO  - Cell Death Dis. 2018 Jun 4;9(6):666. doi: 10.1038/s41419-018-0719-2.