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Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling

Targeted therapies that selectively inhibit certain molecules in cancer cells have been considered promising for cancer treatment. In lung cancer, evidence has suggested that mesenchymal-epithelial transition factor (c-Met) oncoprotein drives cancer progression through its signaling transduction pat...

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Autores principales: Soonnarong, Rapeepun, Putra, Ismail Dwi, Sriratanasak, Nicharat, Sritularak, Boonchoo, Chanvorachote, Pithi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9145792/
https://www.ncbi.nlm.nih.gov/pubmed/35631459
http://dx.doi.org/10.3390/ph15050633
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author Soonnarong, Rapeepun
Putra, Ismail Dwi
Sriratanasak, Nicharat
Sritularak, Boonchoo
Chanvorachote, Pithi
author_facet Soonnarong, Rapeepun
Putra, Ismail Dwi
Sriratanasak, Nicharat
Sritularak, Boonchoo
Chanvorachote, Pithi
author_sort Soonnarong, Rapeepun
collection PubMed
description Targeted therapies that selectively inhibit certain molecules in cancer cells have been considered promising for cancer treatment. In lung cancer, evidence has suggested that mesenchymal-epithelial transition factor (c-Met) oncoprotein drives cancer progression through its signaling transduction pathway. In this paper, we report the downregulation of c-Met by artonin F, a flavonoid isolated from Artocarpus gomezianus. Artonin F was found to be dominantly toxic to lung cancer cells by mediating apoptosis. With regard to its mechanism of action, artonin F downregulated c-Met expression, consequently suppressed the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin signaling, increased Bax expression, decreased Bcl-2 expression, and activated caspase-3. The depletion of c-Met was mediated by ubiquitin-proteasomal degradation following co-treatment with artonin F, with the proteasome inhibitor MG132 reversing its c-Met-targeting effect. The immunoprecipitation analysis revealed that artonin F significantly promoted the formation of the c-Met–ubiquitin complex. Given that ubiquitin-specific protease 8 (USP8) prevents c-Met degradation by deubiquitination, we performed a preliminary in silico molecular docking and observed that artonin F blocked the catalytic site of USP8. In addition, artonin F interacted with the catalytic residues of palmitoylating enzymes. By acting as a competitive inhibitor, artonin F could reduce the degree of palmitoylation of c-Met, which affected its stability and activity. In conclusion, c-Met is critical for cancer cell survival and the failure of chemotherapeutic regimens. This novel information on the c-Met downregulating effect of artonin F will be beneficial for the development of efficient anticancer strategies or targeted therapies.
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spelling pubmed-91457922022-05-29 Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling Soonnarong, Rapeepun Putra, Ismail Dwi Sriratanasak, Nicharat Sritularak, Boonchoo Chanvorachote, Pithi Pharmaceuticals (Basel) Article Targeted therapies that selectively inhibit certain molecules in cancer cells have been considered promising for cancer treatment. In lung cancer, evidence has suggested that mesenchymal-epithelial transition factor (c-Met) oncoprotein drives cancer progression through its signaling transduction pathway. In this paper, we report the downregulation of c-Met by artonin F, a flavonoid isolated from Artocarpus gomezianus. Artonin F was found to be dominantly toxic to lung cancer cells by mediating apoptosis. With regard to its mechanism of action, artonin F downregulated c-Met expression, consequently suppressed the phosphatidylinositol-3 kinase/Akt/mammalian target of rapamycin signaling, increased Bax expression, decreased Bcl-2 expression, and activated caspase-3. The depletion of c-Met was mediated by ubiquitin-proteasomal degradation following co-treatment with artonin F, with the proteasome inhibitor MG132 reversing its c-Met-targeting effect. The immunoprecipitation analysis revealed that artonin F significantly promoted the formation of the c-Met–ubiquitin complex. Given that ubiquitin-specific protease 8 (USP8) prevents c-Met degradation by deubiquitination, we performed a preliminary in silico molecular docking and observed that artonin F blocked the catalytic site of USP8. In addition, artonin F interacted with the catalytic residues of palmitoylating enzymes. By acting as a competitive inhibitor, artonin F could reduce the degree of palmitoylation of c-Met, which affected its stability and activity. In conclusion, c-Met is critical for cancer cell survival and the failure of chemotherapeutic regimens. This novel information on the c-Met downregulating effect of artonin F will be beneficial for the development of efficient anticancer strategies or targeted therapies. MDPI 2022-05-21 /pmc/articles/PMC9145792/ /pubmed/35631459 http://dx.doi.org/10.3390/ph15050633 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Soonnarong, Rapeepun
Putra, Ismail Dwi
Sriratanasak, Nicharat
Sritularak, Boonchoo
Chanvorachote, Pithi
Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling
title Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling
title_full Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling
title_fullStr Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling
title_full_unstemmed Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling
title_short Artonin F Induces the Ubiquitin-Proteasomal Degradation of c-Met and Decreases Akt-mTOR Signaling
title_sort artonin f induces the ubiquitin-proteasomal degradation of c-met and decreases akt-mtor signaling
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9145792/
https://www.ncbi.nlm.nih.gov/pubmed/35631459
http://dx.doi.org/10.3390/ph15050633
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