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A Novel Role for the Tumor Suppressor Gene ITF2 in Tumorigenesis and Chemotherapy Response

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Open AccessArticle

mTORC2/Rac1 Pathway Predisposes Cancer Aggressiveness in IDH1-Mutated Glioma

Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892, USA
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Author to whom correspondence should be addressed.
Cancers 2020, 12(4), 787; https://doi.org/10.3390/cancers12040787 (registering DOI)
Received: 14 February 2020 / Revised: 18 March 2020 / Accepted: 20 March 2020 / Published: 26 March 2020
Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in lower grade gliomas. The neomorphic enzyme activity of IDH mutants leads to tumor formation through epigenetic alteration, dysfunction of dioxygenases, and metabolic reprogramming. However, it remains elusive as to how IDH mutants regulate the pathways associated with oncogenic transformation and aggressiveness. In the present study, by using unbiased transcriptomic profiling, we showed that IDH1 mutations result in substantial changes in the gene sets that govern cellular motility, chemotaxis, and invasion. Mechanistically, rapamycin-insensitive companion of mammalian target of rapamycin (Rictor)/Ras-related C3 botulinum toxin substrate 1 (Rac1) signaling plays an essential role in the motility and proliferation of IDH1-mutated cells by prompting cytoskeleton reorganization, lamellipodia formation, and enhanced endocytosis. Targeting the Rictor/Rac1 pathway suppresses IDH1-mutated cells by limiting endocytosis and cell proliferation. Overall, our findings indicate a novel metabolic reprogramming mechanism of IDH1-mutated cells by exploiting metabolites from the extracellular milieu. Targeting the Rictor/Rac1 pathway could be an alternative therapeutic strategy for IDH1-mutated malignancies.
Keywords: IDH1 mutation; glioma; rac1; mTOR; Rictor; lamellipodia IDH1 mutation; glioma; rac1; mTOR; Rictor; lamellipodia
MDPI and ACS Style

Liu, Y.; Lu, Y.; Li, A.; Celiku, O.; Han, S.; Qian, M.; Yang, C. mTORC2/Rac1 Pathway Predisposes Cancer Aggressiveness in IDH1-Mutated Glioma. Cancers 2020, 12, 787.

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