Knockdown of RWD domain containing 3 inhibits the malignant phenotypes of glioblastoma cells via inhibition of phosphoinositide 3-kinase/protein kinase B signaling.

Glioblastoma is the most common and malignant primary brain tumor. RWD domain containing 3 (RWDD3) has been previously reported to serve a promoting role in pituitary tumors. However, the exact role of RWDD3 in glioblastoma remains unclear. Therefore, the present study aimed to investigate the expression levels of RWDD3 in human glioblastoma tissues and cell lines, as well as to examine the regulatory mechanism of RWDD3 underlying glioblastoma growth and metastasis. The results revealed that RWDD3 was significantly upregulated in glioblastoma tissues compared with normal brain tissues, while high expression of RWDD3 was associated with a shorter survival time of glioblastoma patients. The expression levels of RWDD3 were also higher in the glioblastoma cell lines compared with the normal human astrocyte cell line. Subsequent to knockdown of RWDD3, the proliferation of glioblastoma U87 and U251 cells was significantly decreased, possibly due to the cell cycle arrest at G1 phase, as well as the increased cell apoptosis. Furthermore, downregulation of RWDD3 also suppressed U87 and U251 cell invasion by inhibiting the expression levels of matrix metalloproteinase 2 (MMP2) and MMP9. Molecular mechanism investigation demonstrated that knockdown of RWDD3 significantly downregulated the activity of the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Activation of PI3K/AKT signaling prevented the suppressive effects of RWDD3 downregulation on glioblastoma cell proliferation and migration, concurrent with increased protein levels of MMP2 and MMP9. In conclusion, the current study demonstrated for the first time that inhibition of RWDD3 expression inhibited glioblastoma progression, at least partly, via suppressing the PI3K/AKT signaling activity, and thus RWDD3 may be a novel potential therapeutic target for glioblastoma.