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    -  Kumar S
    -  Banerjee J
    -  Tripathi M
    -  Chandra P S
    -  Dixit AB
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IDH1-R132H-FAT1-ROS-HIF-1α Signaling Pathway Inhibits Glioblastoma Tumor Progression


1 Dr. B.R. Ambedkar Center for Biomedical Research, University of Delhi; Center of Excellence for Epilepsy, AIIMS, New Delhi, India
2 Center of Excellence for Epilepsy; Department of Biophysics, AIIMS, New Delhi, India
3 Center of Excellence for Epilepsy; Department of Neurology, AIIMS, New Delhi, India
4 Center of Excellence for Epilepsy; Department of Neurosurgery, AIIMS, New Delhi, India

Correspondence Address:
Aparna B Dixit,
ACBR, University of Delhi, Delhi - 110 007
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.294541




How to cite this URL:
Kumar S, Banerjee J, Tripathi M, Chandra P S, Dixit AB. IDH1-R132H-FAT1-ROS-HIF-1α Signaling Pathway Inhibits Glioblastoma Tumor Progression. Neurol India [Epub ahead of print] [cited 2020 Oct 23]. Available from: https://www.neurologyindia.com/preprintarticle.asp?id=294541




We congratulate the authors for this study, showing a link between IDH1-R132H, FAT-1 and Hif-1alpha.[1] Also that this signalling pathway contributes to the various findings associated with the role of IDH1-R132H in case of glioblastoma multiforme (GBM). Gliomas are the most frequently encountered brain tumors that are associated with high mortality and disability rate.[2] Glioblastoma (GBM) is the grade IV glioma tumor as per the World Health Organization (WHO) classification and it is the most malignant form of glioma.[3] GBM is characterized by the dysregulation of key signaling pathways linked to growth, proliferation, survival, and apoptosis and, thus, it is important to gain an insight into the mutated genome linked to GBM.[4] One of the most commonly observed mutations in patients diagnosed with GBM is the R132H mutation in Isocitrate Dehydrogenase 1 (IDH1R132H) which is commonly associated with better diagnosis and prognosis.[5] The mechanism by which IDH1R132H exerts its effect in GBM is still not clear, but it is known that this mutation is linked to an increased expression of hypoxia-inducible factor-1α (HIF-1α) in GBM.[6] While there are many reports on the expression of HIF-1α, its associated downstream targets as well as IDH1R132H mutation in GBM, the signaling pathway by which IDH1R132H and HIF-1α are linked still needs to be investigated.

In the given article, Wang has explored the molecular mechanism of IDH1-R132H-induced regulation of HIF-1α in GBM using U87 and U251 GBM cells and xenograft tumor mice.[1] An increase in the expression of HIF-1α, FAT atypical Cadherin 1 (FAT1), and reactive oxygen species (ROS) levels associated with the over-expression of IDH1-R132H has been confirmed in the study. Further, a signaling pathway has been established in which an increase in the levels of HIF-1α associated with IDH1-R132H mutation is attributed to an increase in the expression of FAT1 which promotes the generation of ROS that leads to the upregulation of HIF-1α and suppression of tumor aggressiveness while increasing chemosensitivity to temozolomide (TMZ), which is the first choice of drugs for the treatment of gliomas.[7]

A particularly important finding in this study is the identification of FAT-1 as a bridge that links IDH1-R132H mutation and HIF-1α expression through the promotion of ROS production. Previous reports had identified FAT1 as an upstream regulator of HIF-1α.[8] However, this is the first study that provides a piece of evidence for the role of FAT1 to link IDH1-R132H-induced ROS generation to an increase in the expression of HIF-1α that ultimately leads to a decrease in cell survival in GBM cells.

The given study has confirmed IDH1-R132H to have an inhibitory effect on GBM progression which goes in line with the majority of previous reports.[9] However, several studies have reported otherwise.[10] Thus, it is necessary to validate the results in different cell lines and under different conditions. Besides this, further studies on the mechanism by which ROS leads to the transcriptional up-regulation of HIF-1α and IDH1-R132H regulates FAT1 expression will help provide deeper insights into the IDH1-R132H-FAT1-ROS-HIF-1α signaling pathway and the importance of targeting it as a potential therapeutic intervention of GBM.



 
  References Top

1.
Li L, Zhang M, Feng Y, Wang X. IDH1-R132H suppresses glioblastoma malignancy through FAT1-ROS-HIF-1α signaling. Neurol India 2020;[Ahead of Print].  Back to cited text no. 1
    
2.
Ostrom QT, Gittleman H, Liao P, Vecchione-Koval T, Wolinsky Y, Kruchko C, et al. CBTRUS statistical report: Primary brain and other central nervous system tumors diagnosed in the United States in 2010-2014. Neuro Oncol 2017;19(suppl_5):v1-88.  Back to cited text no. 2
    
3.
Urbańska K, Sokołowska J, Szmidt M, Sysa P. Glioblastoma multiforme - An overview. Con- temp Oncol (Pozn) 2014;18:307-12.  Back to cited text no. 3
    
4.
Mao H, Lebrun DG, Yang J, Zhu VF, Li M. Deregulated signaling pathways in glioblastoma multiforme: Molecular mechanisms and therapeutic targets. Cancer Invest 2012;30:48-56.  Back to cited text no. 4
    
5.
Kim GH, Choi SY, Oh TI, Kan S-Y, Kang H, Lee S, et al. IDH1R132H causes resistance to HDAC inhibitors by in-creasing NANOG in glioblastoma cells. Int J Mol Sci 2019;20:2679. Published 2019 May 31.  Back to cited text no. 5
    
6.
Zhao S, Lin Y, Xu W, Jiang W, Zha Z, Wang P, et al. Glioma-derived mutations in IDH1 dominantly inhibit IDH1 cat-alytic activity and induce HIF-1alpha. Science 2009;324:261-5.  Back to cited text no. 6
    
7.
Bahadur S, Sahu AK, Baghel P, Saha S. Current promising treatment strategy for glioblastoma multiform: A review. Oncol Rev 2019;13:417. Published 2019 Jul 25.  Back to cited text no. 7
    
8.
Madan E, Dikshit B, Gowda SH, Srivastava C, Sarkar C, Chattopadhyay P, et al. FAT1 is a novel upstream regulator of HIF1α and inva- sion of high grade glioma. Int J Cancer 2016;139:2570-82.  Back to cited text no. 8
    
9.
Nie QM, Lin YY, Yang X, Shen L, Guo LM, Que S, et al. IDH1R132H decreases the proliferation of U87 glioma cells through upregulation of microRNA-128a. Mol Med Rep 2015;12:6695-701.  Back to cited text no. 9
    
10.
Wang G, Sai K, Gong F, Yang Q, Chen F, Lin J. Mutation of isocitrate dehydrogenase 1 induces glioma cell proliferation via nuclear factor-κB activation in a hypoxia-inducible factor 1-α de- pendent manner. Mol Med Rep 2014;9:1799-805.  Back to cited text no. 10
    




 

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