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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Autores principales:	Nattamon Hongwiangchan, Nicharat Sriratanasak, Duangdao Wichadakul, Nithikoon Aksorn, Supakarn Chamni, Pithi Chanvorachote
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	lung cancer cancer stem cell Akt mTOR c-Myc renieramycin M Medicine R Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/a4a7e851167242b796d5ca81152f623b
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spelling	oai:doaj.org-article:a4a7e851167242b796d5ca81152f623b2021-11-25T18:39:26ZHydroquinone 5-<i>O</i>-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-Myc10.3390/ph141111121424-8247https://doaj.org/article/a4a7e851167242b796d5ca81152f623b2021-10-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1112https://doaj.org/toc/1424-8247Cancer 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.Nattamon HongwiangchanNicharat SriratanasakDuangdao WichadakulNithikoon AksornSupakarn ChamniPithi ChanvorachoteMDPI AGarticlelung cancercancer stem cellAktmTORc-Mycrenieramycin MMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1112, p 1112 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	lung cancer cancer stem cell Akt mTOR c-Myc renieramycin M Medicine R Pharmacy and materia medica RS1-441
spellingShingle	lung cancer cancer stem cell Akt mTOR c-Myc renieramycin M Medicine R Pharmacy and materia medica RS1-441 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
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.
format	article
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
title	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_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_sort	hydroquinone 5-<i>o</i>-cinnamoyl ester of renieramycin m suppresses lung cancer stem cells by targeting akt and destabilizes c-myc
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/a4a7e851167242b796d5ca81152f623b
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Hydroquinone 5-<i>O</i>-Cinnamoyl Ester of Renieramycin M Suppresses Lung Cancer Stem Cells by Targeting Akt and Destabilizes c-Myc

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