Hydroquinone 5-<i>O</i>-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-Myc
Cancer stem cells (CSCs) are distinct cancer populations with tumorigenic and self-renewal abilities. CSCs are drivers of cancer initiation, progression, therapeutic failure, and disease recurrence. Thereby, novel compounds targeting CSCs offer a promising way to control cancer. In this study, the h...
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| Format: | Article |
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MDPI AG
2021-10-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/14/11/1112 |
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| author | Nattamon Hongwiangchan Nicharat Sriratanasak Duangdao Wichadakul Nithikoon Aksorn Supakarn Chamni Pithi Chanvorachote |
| author_facet | Nattamon Hongwiangchan Nicharat Sriratanasak Duangdao Wichadakul Nithikoon Aksorn Supakarn Chamni Pithi Chanvorachote |
| author_sort | Nattamon Hongwiangchan |
| collection | DOAJ |
| description | Cancer stem cells (CSCs) are distinct cancer populations with tumorigenic and self-renewal abilities. CSCs are drivers of cancer initiation, progression, therapeutic failure, and disease recurrence. Thereby, novel compounds targeting CSCs offer a promising way to control cancer. In this study, the hydroquinone 5-<i>O</i>-cinnamoyl ester of renieramycin M (CIN-RM) was demonstrated to suppress lung cancer CSCs. CIN-RM was toxic to lung cancer cells with a half-maximal inhibitory concentration of around 15 µM. CIN-RM suppressed CSCs by inhibiting colony and tumor spheroid formation. In addition, the CSC population was isolated and treated and the CSCs were dispatched in response to CIN-RM within 24 h. CIN-RM was shown to abolish cellular c-Myc, a central survival and stem cell regulatory protein, with the depletion of CSC markers and stem cell transcription factors ALDH1A1, Oct4, Nanog, and Sox2. For up-stream regulation, we found that CIN-RM significantly inhibited Akt and consequently decreased the pluripotent transcription factors. CIN-RM also inhibited mTOR, while slightly decreasing p-GSK3β (Ser9) but rarely affected the protein kinase C (PKC) signal. Inhibiting Akt/mTOR induced ubiquitination of c-Myc and promoted degradation. The mechanism of how Akt regulates the stability of c-Myc was validated with the Akt inhibitor wortmannin. The computational analysis further confirmed the strong interaction between CIN-RM and the Akt protein with a binding affinity of −10.9 kcal/mol at its critical active site. Taken together, we utilized molecular experiments, the CSC phenotype, and molecular docking methods to reveal the novel suppressing the activity of this compound on CSCs to benefit CSC-targeted therapy for lung cancer treatment. |
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| language | English |
| last_indexed | 2024-03-10T05:10:13Z |
| publishDate | 2021-10-01 |
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| series | Pharmaceuticals |
| spelling | doaj.art-a4a7e851167242b796d5ca81152f623b2023-11-23T00:55:25ZengMDPI AGPharmaceuticals1424-82472021-10-011411111210.3390/ph14111112Hydroquinone 5-<i>O</i>-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-MycNattamon Hongwiangchan0Nicharat Sriratanasak1Duangdao Wichadakul2Nithikoon Aksorn3Supakarn Chamni4Pithi Chanvorachote5Cell-Based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, ThailandCell-Based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, ThailandDepartment of Computer Engineering, Faculty of Engineering, Chulalongkorn University, Bangkok 10330, ThailandDepartment of Clinical Pathology, Faculty of Medicine Vajira Hospital, Navamindradhiraj University, Bangkok 10300, ThailandDepartment of Pharmacognosy and Pharmaceutical Botany, Chulalongkorn University, Bangkok 10330, ThailandCell-Based Drug and Health Products Development Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, ThailandCancer stem cells (CSCs) are distinct cancer populations with tumorigenic and self-renewal abilities. CSCs are drivers of cancer initiation, progression, therapeutic failure, and disease recurrence. Thereby, novel compounds targeting CSCs offer a promising way to control cancer. In this study, the hydroquinone 5-<i>O</i>-cinnamoyl ester of renieramycin M (CIN-RM) was demonstrated to suppress lung cancer CSCs. CIN-RM was toxic to lung cancer cells with a half-maximal inhibitory concentration of around 15 µM. CIN-RM suppressed CSCs by inhibiting colony and tumor spheroid formation. In addition, the CSC population was isolated and treated and the CSCs were dispatched in response to CIN-RM within 24 h. CIN-RM was shown to abolish cellular c-Myc, a central survival and stem cell regulatory protein, with the depletion of CSC markers and stem cell transcription factors ALDH1A1, Oct4, Nanog, and Sox2. For up-stream regulation, we found that CIN-RM significantly inhibited Akt and consequently decreased the pluripotent transcription factors. CIN-RM also inhibited mTOR, while slightly decreasing p-GSK3β (Ser9) but rarely affected the protein kinase C (PKC) signal. Inhibiting Akt/mTOR induced ubiquitination of c-Myc and promoted degradation. The mechanism of how Akt regulates the stability of c-Myc was validated with the Akt inhibitor wortmannin. The computational analysis further confirmed the strong interaction between CIN-RM and the Akt protein with a binding affinity of −10.9 kcal/mol at its critical active site. Taken together, we utilized molecular experiments, the CSC phenotype, and molecular docking methods to reveal the novel suppressing the activity of this compound on CSCs to benefit CSC-targeted therapy for lung cancer treatment.https://www.mdpi.com/1424-8247/14/11/1112lung cancercancer stem cellAktmTORc-Mycrenieramycin M |
| spellingShingle | Nattamon Hongwiangchan Nicharat Sriratanasak Duangdao Wichadakul Nithikoon Aksorn Supakarn Chamni Pithi Chanvorachote Hydroquinone 5-<i>O</i>-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-Myc Pharmaceuticals lung cancer cancer stem cell Akt mTOR c-Myc renieramycin M |
| title | Hydroquinone 5-<i>O</i>-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-Myc |
| title_full | Hydroquinone 5-<i>O</i>-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-Myc |
| title_fullStr | Hydroquinone 5-<i>O</i>-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-Myc |
| title_full_unstemmed | Hydroquinone 5-<i>O</i>-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-Myc |
| title_short | Hydroquinone 5-<i>O</i>-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-Myc |
| title_sort | hydroquinone 5 i o i cinnamoyl ester of renieramycin m suppresses lung cancer stem cells by targeting akt and destabilizes c myc |
| topic | lung cancer cancer stem cell Akt mTOR c-Myc renieramycin M |
| url | https://www.mdpi.com/1424-8247/14/11/1112 |
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