Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations
Epidermal growth factor receptor (EGFR) is the key molecular target for non-small cell lung cancer (NSCLC) due to its major contribution to complex signaling cascades modulating the survival of cancer cells. Targeting EGFR-mediated signaling pathways has been proved as a potential strategy for NSCLC...
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MDPI AG
2019-03-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/4/437 |
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| author | Panupong Mahalapbutr Piyanuch Wonganan Warinthorn Chavasiri Thanyada Rungrotmongkol |
| author_facet | Panupong Mahalapbutr Piyanuch Wonganan Warinthorn Chavasiri Thanyada Rungrotmongkol |
| author_sort | Panupong Mahalapbutr |
| collection | DOAJ |
| description | Epidermal growth factor receptor (EGFR) is the key molecular target for non-small cell lung cancer (NSCLC) due to its major contribution to complex signaling cascades modulating the survival of cancer cells. Targeting EGFR-mediated signaling pathways has been proved as a potential strategy for NSCLC treatment. In the present study, mansonone G (MG), a naturally occurring quinone-containing compound, and its semi-synthetic ether derivatives were subjected to investigate the anticancer effects on human NSCLC cell lines expressing wild-type EGFR (A549) and mutant EGFR (H1975). In vitro cytotoxicity screening results demonstrated that butoxy MG (MG3) exhibits the potent cytotoxic effect on both A549 (IC<sub>50</sub> of 8.54 μM) and H1975 (IC<sub>50</sub> of 4.21 μM) NSCLC cell lines with low toxicity against PCS201-010 normal fibroblast cells (IC<sub>50</sub> of 21.16 μM). Western blotting and flow cytometric analyses revealed that MG3 induces a caspase-dependent apoptosis mechanism through: (i) inhibition of p-STAT3 and p-Akt without affecting upstream p-EGFR and (ii) activation of p-Erk. The 500-ns molecular dynamics simulations and the molecular mechanics combined with generalized Born surface area (MM/GBSA)-based binding free energy calculations suggested that MG3 could possibly interact with STAT3 SH2 domain and ATP-binding pocket of Akt. According to principal component analysis, the binding of MG3 toward STAT3 and Akt dramatically altered the conformation of proteins, especially the residues in the active site, stabilizing MG3 mainly through van der Waals interactions. |
| first_indexed | 2024-03-12T06:20:34Z |
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| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:20:34Z |
| publishDate | 2019-03-01 |
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| series | Cancers |
| spelling | doaj.art-284139fde8944fa4bca79ee7c32f9cbd2023-09-03T02:16:18ZengMDPI AGCancers2072-66942019-03-0111443710.3390/cancers11040437cancers11040437Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical InvestigationsPanupong Mahalapbutr0Piyanuch Wonganan1Warinthorn Chavasiri2Thanyada Rungrotmongkol3Structural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, ThailandDepartment of Pharmacology, Faculty of Medicine, Chulalongkorn University, Pathumwan, Bangkok 10330, ThailandCenter of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, ThailandStructural and Computational Biology Research Unit, Department of Biochemistry, Faculty of Science, Chulalongkorn University, Pathumwan, Bangkok 10330, ThailandEpidermal growth factor receptor (EGFR) is the key molecular target for non-small cell lung cancer (NSCLC) due to its major contribution to complex signaling cascades modulating the survival of cancer cells. Targeting EGFR-mediated signaling pathways has been proved as a potential strategy for NSCLC treatment. In the present study, mansonone G (MG), a naturally occurring quinone-containing compound, and its semi-synthetic ether derivatives were subjected to investigate the anticancer effects on human NSCLC cell lines expressing wild-type EGFR (A549) and mutant EGFR (H1975). In vitro cytotoxicity screening results demonstrated that butoxy MG (MG3) exhibits the potent cytotoxic effect on both A549 (IC<sub>50</sub> of 8.54 μM) and H1975 (IC<sub>50</sub> of 4.21 μM) NSCLC cell lines with low toxicity against PCS201-010 normal fibroblast cells (IC<sub>50</sub> of 21.16 μM). Western blotting and flow cytometric analyses revealed that MG3 induces a caspase-dependent apoptosis mechanism through: (i) inhibition of p-STAT3 and p-Akt without affecting upstream p-EGFR and (ii) activation of p-Erk. The 500-ns molecular dynamics simulations and the molecular mechanics combined with generalized Born surface area (MM/GBSA)-based binding free energy calculations suggested that MG3 could possibly interact with STAT3 SH2 domain and ATP-binding pocket of Akt. According to principal component analysis, the binding of MG3 toward STAT3 and Akt dramatically altered the conformation of proteins, especially the residues in the active site, stabilizing MG3 mainly through van der Waals interactions.https://www.mdpi.com/2072-6694/11/4/437non-small cell lung cancermansonone GapoptosisSTAT3Aktmolecular dynamics simulation |
| spellingShingle | Panupong Mahalapbutr Piyanuch Wonganan Warinthorn Chavasiri Thanyada Rungrotmongkol Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations Cancers non-small cell lung cancer mansonone G apoptosis STAT3 Akt molecular dynamics simulation |
| title | Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations |
| title_full | Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations |
| title_fullStr | Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations |
| title_full_unstemmed | Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations |
| title_short | Butoxy Mansonone G Inhibits STAT3 and Akt Signaling Pathways in Non-Small Cell Lung Cancers: Combined Experimental and Theoretical Investigations |
| title_sort | butoxy mansonone g inhibits stat3 and akt signaling pathways in non small cell lung cancers combined experimental and theoretical investigations |
| topic | non-small cell lung cancer mansonone G apoptosis STAT3 Akt molecular dynamics simulation |
| url | https://www.mdpi.com/2072-6694/11/4/437 |
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