PMID- 32705169
OWN - NLM
STAT- MEDLINE
DCOM- 20210419
LR  - 20211204
IS  - 1791-3004 (Electronic)
IS  - 1791-2997 (Print)
IS  - 1791-2997 (Linking)
VI  - 22
IP  - 3
DP  - 2020 Sep
TI  - Wild‑type IDH1 affects cell migration by modulating the PI3K/AKT/mTOR pathway in 
      primary glioblastoma cells.
PG  - 1949-1957
LID - 10.3892/mmr.2020.11250 [doi]
AB  - Glioblastoma (GBM) is the most common type of brain cancer and has the highest 
      mortality. Dysregulated expression of wild‑type isocitrate dehydrogenase 1 (IDH1) 
      has been demonstrated to promote the progression of primary GBM without 
      accumulating D‑2‑hydroxyglutarate, which differs from IDH1 mutation‑related 
      mechanisms of tumorigenesis. Previous studies have revealed several roles of 
      wild‑type IDH1 in primary GBM, involving proliferation and apoptosis. However, 
      the function of IDH1 in cell migration has not been investigated. In the current 
      study, the results of bioinformatics analysis revealed that IDH1 expression was 
      significantly upregulated in patients with primary GBM. Wound healing and 
      Transwell assays demonstrated that IDH1 overexpression promoted cell migration in 
      primary GBM cells and that IDH1 knockdown hindered this process. Furthermore, 
      alpha‑ketoglutarate (alpha‑KG), which is the main product of IDH1‑catalyzed reactions, 
      was significantly decreased by IDH1 knockdown and upregulated by IDH1 
      overexpression. alpha‑KG treatment significantly increased the migration of primary 
      GBM cells. Additionally, RNA sequence analysis of patients with primary GBM 
      reported significant alterations in the expression of phosphoinositide 3‑kinase 
      (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) 
      pathway‑regulated genes, including Myc, Snail family transcriptional repressor 2 
      and Twist‑related protein 1, which are primarily cell migration regulatory 
      factors. Western blotting revealed that the overexpression or knockdown of IDH1 
      promoted or inhibited the PI3K/AKT/mTOR pathway, respectively. alpha‑KG treatment of 
      primary GBM cells also promoted the PI3K/AKT/mTOR pathway. Furthermore, 
      IDH1‑overexpressing and alpha‑KG‑treated U87 cells were incubated with rapamycin, an 
      mTOR‑specific inhibitor, and the results revealed that rapamycin treatment 
      reversed the increased cell migration caused by IDH1 overexpression and alpha‑KG 
      treatment. The results indicated that IDH1 regulated the migration of primary GBM 
      cells by altering alpha‑KG levels and that the function of the IDH1/alpha‑KG axis may 
      rely on PI3K/AKT/mTOR pathway regulation.
FAU - Shen, Xiaopeng
AU  - Shen X
AD  - Anhui Provincial Key Laboratory of the Conservation and Exploitation of 
      Biological Resources, College of Life Sciences, Anhui Normal University, Wuhu, 
      Anhui 241000, P.R. China.
FAU - Wu, Shen
AU  - Wu S
AD  - Anhui Provincial Key Laboratory of the Conservation and Exploitation of 
      Biological Resources, College of Life Sciences, Anhui Normal University, Wuhu, 
      Anhui 241000, P.R. China.
FAU - Zhang, Jingyi
AU  - Zhang J
AD  - Anhui Provincial Key Laboratory of the Conservation and Exploitation of 
      Biological Resources, College of Life Sciences, Anhui Normal University, Wuhu, 
      Anhui 241000, P.R. China.
FAU - Li, Meng
AU  - Li M
AD  - Anhui Provincial Key Laboratory of the Conservation and Exploitation of 
      Biological Resources, College of Life Sciences, Anhui Normal University, Wuhu, 
      Anhui 241000, P.R. China.
FAU - Xu, Feng
AU  - Xu F
AD  - Anhui Provincial Key Laboratory of the Conservation and Exploitation of 
      Biological Resources, College of Life Sciences, Anhui Normal University, Wuhu, 
      Anhui 241000, P.R. China.
FAU - Wang, Ao
AU  - Wang A
AD  - Anhui Provincial Key Laboratory of the Conservation and Exploitation of 
      Biological Resources, College of Life Sciences, Anhui Normal University, Wuhu, 
      Anhui 241000, P.R. China.
FAU - Lei, Yang
AU  - Lei Y
AD  - Department of Inspection, Wuhu Center for Disease Control and Prevention, Wuhu, 
      Anhui 241000, P.R. China.
FAU - Zhu, Guoping
AU  - Zhu G
AD  - Anhui Provincial Key Laboratory of the Conservation and Exploitation of 
      Biological Resources, College of Life Sciences, Anhui Normal University, Wuhu, 
      Anhui 241000, P.R. China.
LA  - eng
PT  - Journal Article
DEP - 20200618
PL  - Greece
TA  - Mol Med Rep
JT  - Molecular medicine reports
JID - 101475259
RN  - EC 1.1.1.41 (Isocitrate Dehydrogenase)
RN  - EC 1.1.1.42. (IDH1 protein, human)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.1.137 (Phosphatidylinositol 3-Kinase)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Brain Neoplasms/*genetics/metabolism
MH  - Cell Line, Tumor
MH  - Cell Movement/drug effects
MH  - Gene Expression Profiling
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Gene Knockdown Techniques
MH  - Glioblastoma/*genetics/metabolism
MH  - Humans
MH  - Isocitrate Dehydrogenase/*genetics/*metabolism
MH  - Phosphatidylinositol 3-Kinase/metabolism
MH  - Proto-Oncogene Proteins c-akt/metabolism
MH  - Sequence Analysis, RNA
MH  - Sirolimus/pharmacology
MH  - TOR Serine-Threonine Kinases/metabolism
MH  - *Up-Regulation
PMC - PMC7411459
OTO - NOTNLM
OT  - primary glioblastoma
OT  - isocitrate dehydrogenase 1
OT  - alpha-ketoglutarate
OT  - cell migration
OT  - phosphoinositide 3-kiase/protein kinase B/mammalian target of rapamycin pathway
EDAT- 2020/07/25 06:00
MHDA- 2021/04/20 06:00
PMCR- 2020/06/18
CRDT- 2020/07/25 06:00
PHST- 2020/01/13 00:00 [received]
PHST- 2020/05/18 00:00 [accepted]
PHST- 2020/07/25 06:00 [entrez]
PHST- 2020/07/25 06:00 [pubmed]
PHST- 2021/04/20 06:00 [medline]
PHST- 2020/06/18 00:00 [pmc-release]
AID - mmr-22-03-1949 [pii]
AID - 10.3892/mmr.2020.11250 [doi]
PST - ppublish
SO  - Mol Med Rep. 2020 Sep;22(3):1949-1957. doi: 10.3892/mmr.2020.11250. Epub 2020 Jun 
      18.