Inference of Subpathway Activity Profiles Reveals Metabolism Abnormal Subpathway Regions in Glioblastoma Multiforme

Abstract

Glioblastoma, also known as glioblastoma multiforme (GBM), is the most malignant form of glioma and represents 81% of malignant brain and central nervous system (CNS) tumors. Like most cancers, GBM causes metabolic recombination to promote cell survival, proliferation, and invasion of cancer cells. In this study, we propose a method for constructing the metabolic subpathway activity score matrix to accurately identify abnormal targets of GBM metabolism. By integrating gene expression data from different sequencing methods, our method identified 25 metabolic subpathways that were significantly abnormal in the GBM patient population, and most of these subpathways have been reported to have an effect on GBM. Through the analysis of 25 GBM-related metabolic subpathways, we found that (S)-2,3-Epoxysqualene, which was at the central region of the sterol biosynthesis subpathway, may have a greater impact on the entire pathway, suggesting a potential high association with GBM. Analysis of CCK8 cell activity indicated that (S)-2,3-Epoxysqualene can indeed inhibit the activity of U87-MG cells. By flow cytometry, we demonstrated that (S)-2,3-Epoxysqualene not only arrested the U87-MG cell cycle in the G0/G1 phase but also induced cell apoptosis. These results confirm the reliability of our proposed metabolic subpathway identification method and suggest that (S)-2,3-Epoxysqualene has potential therapeutic value for GBM. In order to make the method more broadly applicable, we have developed an R system package crmSubpathway to perform disease-related metabolic subpathway identification and it is freely available on the GitHub ( https://github.com/hanjunwei-lab/crmSubpathway ).

Squalene epoxidase promotes the chemoresistance of colorectal cancer via (S)-2,3-epoxysqualene-activated NF-κB

“…(S)-2,3-epoxysqualene is the direct product of squalene catalyzed by SQLE in cholesterol metabolism, however, little information is currently available about the value of (S)-2,3-epoxysqualene in cancer research. Only one previous study has reported that (S)-2,3-epoxysqualene would arrest the cell cycle in the G0/G1 phase and induce cell apoptosis in glioblastoma multiforme [ 22 ]. In our study, we experimentally demonstrated that (S)-2,3-epoxysqualene treatment would result in the activation of NF-κB pathway.…”

“…SQLE, as the second key enzyme in cholesterol biosynthesis, catalyzes the initial oxygenation step [ 20 ]. Squalene is converted by SQLE to (S)-2,3-epoxysqualene during cholesterol synthesis, but limited information is currently available regarding the significance of (S)-2,3-epoxysqualene in cancer research [ 21 , 22 ]. SQLE is overexpressed in several cancers and the high expression of SQLE is closely related to the poor prognosis of cancer patients, including CRC [ 20 , 23 ].…”

Polyurethane scaffold-based 3D lung cancer model recapitulates in vivo tumor biological behavior for nanoparticulate drug screening

“…After cultivated in plates or scaffolds for 24 and 48 h, the cells were harvested, washed and finally resuspended in DPBS with RNAse. Cell cycle was tested using propidium iodide (PI) staining, apoptosis was measured using annexin V-FITC and PI double staining as described previously [ 34 ]. The analysis was carried out by an ACEA NovoCyte flow cytometer (ACEA Biosciences Inc.), and a negative control was prepared to set the sampling parameters of the flow cytometer and the range of the gate.…”