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01.12.2012 | Primary research | Ausgabe 1/2012 Open Access

Cancer Cell International 1/2012

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

Zeitschrift:
Cancer Cell International > Ausgabe 1/2012
Autoren:
Hiroko Tabunoki, Naoki Saito, Khanit Suwanborirux, Kornvika Charupant, Jun-ichi Satoh
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1475-2867-12-14) contains supplementary material, which is available to authorized users.

Competing interests

The authors declare that they have no competing interests.

Authors’ contribution

HT carried out the molecular biological experiments. JS analyzed the microarray data and drafted the manuscript. NS, KS, and KC prepared 1,2,3,4-tetrahydroisoquinolines 1a, 2a, and 3. All authors have read and approved the final manuscript.

Abstract

Background

Glioblastoma is the most aggressive form of brain tumors showing resistance to treatment with various chemotherapeutic agents. The most effective way to eradicate glioblastoma requires the concurrent inhibition of multiple signaling pathways and target molecules involved in the progression of glioblastoma. Recently, we obtained a series of 1,2,3,4-tetrahydroisoquinoline alkaloids with potent anti-cancer activities, including ecteinascidin-770 (ET-770; the compound 1a) and renieramycin M (RM; the compound 2a) from Thai marine invertebrates, together with a 2’-N-4”-pyridinecarbonyl derivative of ET-770 (the compound 3). We attempted to characterize the molecular pathways responsible for cytotoxic effects of these compounds on a human glioblastoma cell line U373MG.

Methods

We studied the genome-wide gene expression profile on microarrays and molecular networks by using pathway analysis tools of bioinformatics.

Results

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.

Conclusion

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.
Zusatzmaterial
Additional file 1: The principal component analysis of RMA-normalized microarray data. (PPT 173 KB)
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Additional file 2: Table S1: The set of 426 genes downregulated in U373MG cells following exposure to ET-770 (the compound 1a). (XLS 76 KB)
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Additional file 3: Table S2: The set of 45 genes upregulated in U373MG cells following exposure to ET-770 (the compound 1a). (XLS 26 KB)
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Additional file 4: Table S3: The set of 417 genes downregulated in U373MG cells following exposure to ET-770 derivative (the compound 3). (XLS 76 KB)
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Additional file 5: Table S4: The set of 84 genes upregulated in U373MG cells following exposure to ET-770 derivative (the compound 3). (XLS 32 KB)
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Additional file 6: Table S5: The set of 274 genes downregulated in U373MG cells following exposure to RM (the compound 2a). (XLS 64 KB)
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Additional file 7: Table S6: The set of 9 genes upregulated in U373MG cells following exposure to RM (the compound 2a). (XLS 30 KB)
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Additional file 8: Table S7: The set of 196 downregulated genes and 6 upregulated genes in U373MG cells shared among the compounds 1a, 2a, and 3 treatments. (XLS 52 KB)
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Additional file 9: The PANTHER molecular network of downregulated genes in U373MG cells following exposure to ET-770, the compound 1a. (PPT 381 KB)
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Additional file 10: The IF analysis of molecular network of downregulated genes in U373MG cells following exposure to ET-770, the compound 1a. (PPT 126 KB)
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Authors’ original file for figure 1
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Authors’ original file for figure 2
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Authors’ original file for figure 3
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Authors’ original file for figure 4
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Authors’ original file for figure 5
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Authors’ original file for figure 6
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Authors’ original file for figure 7
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Authors’ original file for figure 8
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Authors’ original file for figure 9
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