Fig 2: A working model of hypoxia and Hif-1a on mESC differentiation. Hypoxia suppressed the mesendoderm differentiation and promoted the ectoderm differentiation of mESCs by inhibiting the Wnt/ß-Catenin pathway. The inhibition of the Wnt/ß-Catenin pathway was through the PI3K/Akt/GSK3ß axis. Hif-1a, on the contrary, promoted the mesendoderm differentiation and suppressed the ectoderm differentiation, which was at least partially through the Wnt/ß-Catenin pathway as well

Fig 3: Phosphoinositide 3-kinase/AKT/mTOR pathway activity was altered by changes in the levels of IDH1 and a-KG in primary GBM cells. (A) p-AKT (Ser473) was promoted by IDH1 overexpression in U87 cells. (B) Semi-quantification of the expression levels from part (A). (C) p-AKT (Ser473) was decreased by IDH1 knockdown in U87 cells. (D) Semi-quantification of expression levels from part (C). (E) p-AKT (Ser473) was promoted by a-KG treatment in a dose-dependent manner in U87 cells. (F) Semi-quantification of the expression levels from part (E). (G) p-mTOR (Ser2448) was promoted by IDH1 overexpression in U87 cells. (H) Semi-quantification of the expression levels from (G). (I) p-mTOR (Ser2448) was repressed by IDH1 knockdown in U87 cells. (J) Semi-quantification of the expression levels from part (I). (K) p-mTOR (Ser2448) was promoted by a-KG treatment in a dose-dependent manner in U87 cells. a-KG treatment lasted for 24 h. (L) Semi-quantification of the expression levels from part (K). *P<0.05, **P<0.01, ***P<0.001 vs. shScramble/Ctrl/0 mM. p, phosphorylated; AKT, protein kinase B; IDH1, isocitrate dehydrogenase 1; a-KG, a-ketoglutarate; GBM, glioblastoma; Ser, serine; Ctrl, control; IDH1-OE, IDHI1 overexpression cell line; shRNA, short hairpin RNA; shScramble, scramble shRNA; shIDH-1/2, IDH1 shRNA plasmids 1/2.

Fig 4: A working model of wild-type IDH1 in primary GBM cells. IDH1 is the enzyme that catalyzes a-KG production from isocitrate. Wild-type IDH1 promotes the activation of the PI3K/AKT/mTOR pathway by affecting a-KG levels. IDH1 and a-KG may regulate primary GBM cell migration by modulating the PI3K/AKT/mTOR pathway. IDH1, isocitrate dehydrogenase 1; GBM, glioblastoma; a-KG, a-ketoglutarate; PI3K, phosphoinositide 3-kinase; AKT, protein kinase B; mTOR, mammalian target of rapamycin; P, phosphorylated.