Cancers, Vol. 12, Pages 787: mTORC2/Rac1 Pathway Predisposes Cancer Aggressiveness in IDH1-Mutated Glioma

Cancers, Vol. 12, Pages 787: mTORC2/Rac1 Pathway Predisposes Cancer Aggressiveness in IDH1-Mutated Glioma Cancers doi: 10.3390/cancers12040787 Authors: Yang Liu Yanxin Lu Aiguo Li Orieta Celiku Sue Han Mingyu Qian Chunzhang Yang 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 str...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research