Osthole Inhibits Insulin-like Growth Factor-1-Induced Epithelial to Mesenchymal Transition via the Inhibition of PI3K/Akt Signaling Pathway in Human Brain Cancer Cells

Abstract

Glioblastoma multiforme (GBM) is one of the most lethal types of tumors and highly metastatic and invasive. The epithelial-to-mesenchymal transition (EMT) is the crucial step for cancer cells to initiate the metastasis and could be induced by many growth factors. In this study, we found that GBM8401 cells were converted to fibroblastic phenotype and the space between the cells became expanded in response to insulin-like growth factor-1 (IGF-1) treatment. Epithelial markers were downregulated and mesenchymal markers were upregulated simultaneously after IGF-1 treatment. Our results illustrate that IGF-1 was able to induce EMT in GBM8401 cells. Osthole would reverse IGF-1-induced morphological changes, upregulated the expression of epithelial markers, and downregulated the expression of mesenchymal markers. Moreover, wound-healing assay also showed that osthole could inhibit IGF-1-induced migration of GBM8401 cells. By using dual-luciferase reporter assay and real-time PCR, we demonstrated that osthole inhibited IGF-1-induced EMT at the transcriptional level. Our study found that osthole decreased the phosphorylation of Akt and GSK3β and recovered the GSK3β bioactivity in inhibiting EMT transcription factor Snail and Twist expression. These results showed that osthole inhibited IGF-1-induced EMT by blocking PI3K/Akt pathway. We hope that osthole can be used in anticancer therapy and be a new therapeutic medicine for GBM in the future.

A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition

“…This decreased expression subsequently promoted E-cadherin expression, reduced vimentin expression, restored the cells' polygonal shape, and stimulated the mesenchymal-epithelial transition (MET). 28,29 Twist expression was suppressed after Figure 1. The characteristics, regulators and effects of the epithelial-mesenchymal transition (EMT).…”

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

“…[96,97] Therefore, IGF-1R tyrosine kinase inhibitors or IGF-1 inhibitors, such as osthole, have been used to inhibit GBM proliferation, migration and EMT. [97,98] In a recent study of 218 cases of human GBM, IGF-1R overexpression was reported as an independent prognostic factor associated with shorter survival time and a less favorable response to temozolomide. [99] C-MET expression levels correlate with tumor grade in CNS malignancies, [100] and its activation also mediates EMTpromoting signals in cancer cells via class I A PI3K.…”

Osthole Preconditioning Protects Rats Against Renal Ischemia-Reperfusion Injury

“…It has been demonstrated that inflammation plays an important role in renal I/R injury [4e6] and that osthole has the effect of suppressing inflammation [16]. Therefore, we selectively analyzed the expression of TNF-a, IL-6 and 1L-8 in renal tissues after I/R insult by means of real-time PCR.…”

“…However, to date, the effects and potential mechanism of osthole on renal I/R injury remain unclear. Moreover, osthole has been demonstrated to regulate the PI3K/Akt signaling [16]. Hence, the present study explored whether osthole pre-treatment has protective effects on I/R-induced renal injury by suppressing NF-kB activation, and, if so, whether suppression of NF-kB activation is associated with PI3K/Akt signaling.…”