Molecular network profiling of U373MG human glioblastoma cells following induction of apoptosis by novel marine-derived anti-cancer 1,2,3,4-tetrahydroisoquinoline alkaloids

We studied the genome-wide gene expression profile on microarrays and molecular networks by using pathway analysis tools of bioinformatics.All of these compounds induced apoptosis of U373MG cells at nanomolar concentrations. The compound 3 reduced the expression of 417 genes and elevated the levels of 84 genes, while ET-770 downregulated 426 genes and upregulated 45 genes. RM decreased the expression of 274 genes and increased the expression of 9 genes. The set of 196 downregulated genes and 6 upregulated genes showed an overlap among all the compounds, suggesting an existence of the common pathways involved in induction of apoptosis. We identified the ErbB (EGFR) signaling pathway as one of the common pathways enriched in the set of downregulated genes, composed of PTK2, AKT3, and GSK3B serving as key molecules that regulate cell movement and the nervous system development. Furthermore, a GSK3B-specific inhibitor induced apoptosis of U373MG cells, supporting an anti-apoptotic role of GSK3B.Molecular network analysis is a useful approach not only to characterize the glioma-relevant pathways but also to identify the network-based effective drug targets.Glioblastoma, World Health Organization (WHO) grade IV, is the most common and aggressive form of primary malignant brain tumors affecting the adult human brain. Glioblastoma is categorized into two distinct subtypes that develop through different genetic and molecular pathways, designated as primary glioblastoma and secondary glioblastoma [1]. Primary glioblastoma that develops without precursor lesions shows an amplification of the epidermal growth factor receptor (EGFR) gene more frequently than secondary glioblastoma that generates via the stepwise progression from the pre-existing low-grade glioma. EGFR amplification in primary glioblastoma is often associated with the expression of EGFRvIII, a ligand-independent constitutively active mutant of EGFR, capable of persistently activating the phosphatidylinositol 3-ki