We have previously shown that compound-7g inhibits colorectal cancer cell proliferation and survival by inducing cell cycle arrest and PI3K/AKT/mTOR pathway blockage. However, whether it has the ability to exert antitumor activity in other cancer cells and what is the exact molecular mechanism for its antiproliferation effect remained to be determined. In the present study, compound-7g exhibited strong activity in suppressing proliferation and growth of glioblastoma cells. The inhibitor selectively downregulated F-box protein SKP2 expression and upregulated cell cycle inhibitor p27, and then resulted in G1 cell cycle arrest. Mechanism analysis revealed that compound-7g also provokes the down-regulation of E2F-1, which acts as a transcriptional factor of SKP2. Further results indicated that compound-7g induced an increase of LC3B-II and p62, which causes a suppression of fusion between autophagosome and lysosome. Moreover, compound-7g mediated autophagic flux blockage promoted accumulation of ubiquitinated proteins and then led to endoplasmic reticulum stress. Our study thus demonstrated that pharmacological inactivation of E2F-1-SKP2-p27 axis is a promising target for restricting cancer progression.

PPP3CB belongs to the phosphoprotein phosphatases (PPPs) group. Although the majority of the PPP family play important roles in the epithelial-to-mesenchymal transition (EMT) of tumor cells, little is known about the function of PPP3CB in the EMT process. Here, we found PPP3CB had high expression in kidney mesenchymal-like cells compared with kidney epithelial-like cells. Knock-down of PPP3CB downregulated epithelial marker E-cadherin and upregulated mesenchymal marker Vimentin, promoting the transition of cell states from epithelial to mesenchymal and reorganizing the actin cytoskeleton which contributed to cell migration. Conversely, overexpression of PPP3CB reversed EMT and inhibited migration of tumor cells. Besides, in vitro and in vivo experiments indicated that the loss of PPP3CB suppressed the tumor growth. However, the deletion of the phosphatase domain of PPP3CB showed no effect on the expression of E-cadherin, migration, and G401 cell proliferation. Together, we demonstrate that PPP3CB inhibits G401 cell migration through regulating EMT and promotes cell proliferation, which are both associated with the phosphatase activity of PPP3CB.