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IDH1-R132H-FAT1-ROS-HIF-1α Signaling Pathway Inhibits Glioblastoma Tumor Progression
Sonali Kumar1, Jyotirmoy Banerjee2, Manjari Tripathi3, P Sarat Chandra4, Aparna B Dixit1
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
Aparna B Dixit,
ACBR, University of Delhi, Delhi - 110 007
Source of Support: None, Conflict of Interest: None
We congratulate the authors for this study, showing a link between IDH1-R132H, FAT-1 and Hif-1alpha. 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. 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. 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. 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. 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. 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. 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.
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. 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. However, several studies have reported otherwise. 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.
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