β-hydroxybutyrate inhibits cellular proliferation, EMT, stemness, migration, and invasion in glioma cells

Glioma is the most common and account for 81% of intracranial malignancies. Ketogenic dietary intervention in patients with glioma has been more and more popular. However, the current research mechanism on β-hydroxybutyrate (BHB) and glioma is not clear, and we have explored the mechanism of BHB inhibiting glioma. Western blot, polymerase chain reaction (PCR), and immunofluorescence were used to study the relationship between BHB and proliferation, stemness, epithelial mesenchymal transformation, migration, and invasion of glioma U251 cells. In the present study, our results showed that BHB treatment downregulated the expressions of epithelial-to-mesenchymal transition (EMT)-related proteins including N-cadherin and vimentin, while upregulated the expression of E-cadherin in U251 glioma cells, when compared with control group. Meanwhile, the expressions of matrix metallopeptidase (MMP)2, MMP9, and vascular endothelial growth factor A (VEGFA) proteins were decreased in BHB-treated group. The expression levels of TGF-β, p-phosphatidylinositol-3-kinase (PI3K), p-protein kinase B (Akt), p-glycogen synthase kinase 3β (GSK-3β), Wnt5a, β-catenin, and Snail were decreased in the BHB-treated group, as our results showed. Additionally, BHB treatment downregulated the expressions of p-Janus kinase 2 (JAK2) and p-signal transducer and activator of transcription 3 (STAT3) proteins, which are related to migration of glioma cells, respectively. In addition, BHB inhibited glioma stemness genes such as CD133, ALDH1, SOX2, and Olig2. Altogether, present study concluded that BHB inhibited proliferation, EMT, and migration of glioma cells by inhibiting transforming growth factor (TGF)-β/PI3K/Akt/GSK-3β, Wnt5a/β-catenin/Snail, and interleukin (IL)-6/JAK2/STAT3 signaling pathways, therefore, with a diet containing BHB will benefit the glioma patients.