Inhibition of PLK4 might enhance the anti‐tumour effect of bortezomib on glioblastoma via PTEN/PI3K/AKT/mTOR signalling pathway

Abstract

GBM) is one of the most common aggressive cancers that occurs in the adult brain, and the survival period after initial diagnosis is only 12-15 months. 1 GBM accounts for nearly 70% of all adult brain tumours. 2 Effective treatment for GBM, which is characterized by rapid proliferation ability and highly infiltrative growth, is still lacking. 3 Bortezomib is a selective and reversible proteasome inhibitor that was first developed for the treatment of inflammation and cachexia in the late 90 seconds. 4 Studies using several tumour cells lines from the National Cancer Institute (NCI) confirmed its potency and wide range of anti-tumour effects. 5 Bortezomib was initially approved by US Food and Abstract Glioblastoma (GBM) is one of the most common aggressive cancers of the central nervous system in adults with a high mortality rate. Bortezomib is a boronic acidbased potent proteasome inhibitor that has been actively studied for its anti-tumour effects through inhibition of the proteasome. The proteasome is a key component of the ubiquitin-proteasome pathway that is critical for protein homeostasis, regulation of cellular growth, and apoptosis. Overexpression of polo-like kinase 4 (PLK4) is commonly reported in tumour cells and increases their invasive and metastatic abilities.In this study, we established a cell model of PLK4 knockdown and overexpression in LN-18, A172 and LN-229 cells and found that knockdown of PLK4 expression enhanced the anti-tumour effect of bortezomib. We further found that this effect may be mediated by the PTEN/PI3K/AKT/mTOR signalling pathway and that the apoptotic and oxidative stress processes were activated, while the expression of matrix metalloproteinases (MMPs) was down-regulated. Similar phenomenon was observed using in vitro experiments. Thus, we speculate that PLK4 inhibition may be a new therapeutic strategy for GBM.

Polo-Like Kinase 4’s Critical Role in Cancer Development and Strategies for Plk4-Targeted Therapy

“…In addition, the anti-tumor effect of bortezomib was enhanced after Plk4 knockdown in three (LN-18, A172 and LN-229) GBM cell lines and xenograft experiments. Further investigations indicate that this effect may be mediated by the PTEN/PI3K/AKT/mTOR signaling pathway (170). Thus, these findings indicated that Plk4 is a promising therapeutic target for GBM.…”

The Role of Mammalian Target of Rapamycine Signaling Pathway in Central Nervous System Cancers: A Review

“…Nowadays, a new generation of mTOR inhibitors is under investigation that acts as Adenosine Triphosphate (ATP) analogues in competition with ATP to bind to the mTOR protein. Interestingly, unlike rapamycin and its analogues, this generation of mTOR inhibitors is able to inhibit both the mTORC1 and mTORC2 complexes [69].…”

Role of Polo-Like Kinase 4 (PLK4) in Epithelial Cancers and Recent Progress in its Small Molecule Targeting for Cancer Management

“…Although the role of PLK4 has been studied in several cancers (37)(38)(39)(40), to narrow our scope for this review, we have focused on epithelial cancers. Although PLK4 has not been found to be commonly mutated in human neoplasms, due to its frequently aberrant expression and its importance in regulating the centriole and centrosome duplication cycle and links to many other crucial proteins, researchers have focused on PLK4 as a potential cancer biomarker.…”