Effect and Mechanism of Z-guggulsterone Inhibit the Proliferation of Glioblastoma Cells Based on the Crosstalk Between YAP and Akt/mTOR Pathway

OBJECTIVE To explore the effect and mechanism of Z-guggulsterone(Z-GS) regulating glioblastoma cells proliferation through YAP and Akt/mTOR pathway crosstalk.

METHODS Determined the expression of Mst1, Lats1, YAP, p-YAP, Akt, p-Akt^Thr308, p-Akt^Ser473, mTOR, p-mTOR^Ser2448 and p-mTOR^Ser2481 proteins in glioma clinical specimens by immunohistochemical staining. Screened the glioblastoma cell lines with high expression of above proteins by Western blotting. After treatment of human glioblastoma T98G cells with Z-GS, cell viability was assessed using the CCK-8 method; and the proliferation of T98G cells was examined through plate cloning experiments; the expression of Mst1, p-Mst1, Lats1, p-Lats1, YAP, p-YAP, PTEN, Akt, p-Akt^Thr308, p-Akt^Ser473, mTOR, p-mTOR^Ser2448 and p-mTOR^Ser2481 proteins in T98G cells was determined by Western blotting.

RESULTS Compared with normal brain tissue, the positive expression of YAP, p-YAP, Akt, p-Akt^Thr308, mTOR and p-mTOR^Ser2448 proteins in grade IV glioma tissue was stronger. The positive expression of p-YAP, Akt, and p-mTOR^Ser2448 was significantly correlated with the glioblastoma tissue. The expression level of above proteins in T98G cells was higher among the four glioblastoma cell lines. After T98G cells treatment with Z-GS(12.5, 25, 50 μmol·L⁻¹) for 24 h, there was no cytotoxic effects and it could inhibit the cell proliferation. Meanwhile, Z-GS significantly reduced the proteins expression of YAP, p-YAP and the level of p-mTOR^Ser2448, and significantly increased the level of p-Mst1 and p-Lats1 in T98G cells.

CONCLUSION Z-GS may inhibit the proliferation of human glioblastoma cells by restoring Hippo pathway activity and downregulating mTORC1 activity.