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ReishiMax inhibits mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells

Ganoderma lucidum (G. lucidum) extracts, as dietary supplements, have been found to exert potent anticancer activity, which is attributed to the presence of polysaccharides and triterpenes. However, the molecular mechanism underlying the anticancer action of G. lucidum extracts remains to be investi...

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Autores principales: Sohretoglu, Didem, Zhang, Chao, Luo, Jun, Huang, Shile
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799808/
https://www.ncbi.nlm.nih.gov/pubmed/31637001
http://dx.doi.org/10.1038/s41392-019-0056-7
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author Sohretoglu, Didem
Zhang, Chao
Luo, Jun
Huang, Shile
author_facet Sohretoglu, Didem
Zhang, Chao
Luo, Jun
Huang, Shile
author_sort Sohretoglu, Didem
collection PubMed
description Ganoderma lucidum (G. lucidum) extracts, as dietary supplements, have been found to exert potent anticancer activity, which is attributed to the presence of polysaccharides and triterpenes. However, the molecular mechanism underlying the anticancer action of G. lucidum extracts remains to be investigated. Here, we show that ReishiMax GLp, containing G. lucidum polysaccharides and triterpenes (GLPT), inhibited cell proliferation and induced cell death in human lung cancer cells (A549 and A427) and simultaneously suppressed the signaling pathways of mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2), respectively. Mechanistically, GLPT downregulated the phosphorylation and protein levels of insulin-like growth factor 1 receptor (IGFR) and phosphoinositide 3-kinase (PI3K) as well as the protein level of RAS homolog enriched in brain (Rheb). In addition, GLPT also activated the AMP-activated protein kinase (AMPK) network. This was evidenced by observations that GLPT increased the phosphorylation of AMPKα (T172) and its substrates tuberous sclerosis complex 2 (TSC2, S1387) and regulatory-associated protein of mTOR (raptor, S792). Ectopic expression of dominant-negative AMPKα partially mitigated the inhibitory effect of GLPT on mTORC1, indicating that GLPT inhibits mTORC1 partly by activating AMPK. The results suggest that G. lucidum extracts exert anticancer action at least partly by suppressing mTORC1/2 signaling via activation of AMPK and inhibition of IGFR/PI3K/Rheb in tumor cells.
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spelling pubmed-67998082019-10-21 ReishiMax inhibits mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells Sohretoglu, Didem Zhang, Chao Luo, Jun Huang, Shile Signal Transduct Target Ther Article Ganoderma lucidum (G. lucidum) extracts, as dietary supplements, have been found to exert potent anticancer activity, which is attributed to the presence of polysaccharides and triterpenes. However, the molecular mechanism underlying the anticancer action of G. lucidum extracts remains to be investigated. Here, we show that ReishiMax GLp, containing G. lucidum polysaccharides and triterpenes (GLPT), inhibited cell proliferation and induced cell death in human lung cancer cells (A549 and A427) and simultaneously suppressed the signaling pathways of mammalian target of rapamycin complexes 1 and 2 (mTORC1 and mTORC2), respectively. Mechanistically, GLPT downregulated the phosphorylation and protein levels of insulin-like growth factor 1 receptor (IGFR) and phosphoinositide 3-kinase (PI3K) as well as the protein level of RAS homolog enriched in brain (Rheb). In addition, GLPT also activated the AMP-activated protein kinase (AMPK) network. This was evidenced by observations that GLPT increased the phosphorylation of AMPKα (T172) and its substrates tuberous sclerosis complex 2 (TSC2, S1387) and regulatory-associated protein of mTOR (raptor, S792). Ectopic expression of dominant-negative AMPKα partially mitigated the inhibitory effect of GLPT on mTORC1, indicating that GLPT inhibits mTORC1 partly by activating AMPK. The results suggest that G. lucidum extracts exert anticancer action at least partly by suppressing mTORC1/2 signaling via activation of AMPK and inhibition of IGFR/PI3K/Rheb in tumor cells. Nature Publishing Group UK 2019-06-28 /pmc/articles/PMC6799808/ /pubmed/31637001 http://dx.doi.org/10.1038/s41392-019-0056-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Sohretoglu, Didem
Zhang, Chao
Luo, Jun
Huang, Shile
ReishiMax inhibits mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells
title ReishiMax inhibits mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells
title_full ReishiMax inhibits mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells
title_fullStr ReishiMax inhibits mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells
title_full_unstemmed ReishiMax inhibits mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells
title_short ReishiMax inhibits mTORC1/2 by activating AMPK and inhibiting IGFR/PI3K/Rheb in tumor cells
title_sort reishimax inhibits mtorc1/2 by activating ampk and inhibiting igfr/pi3k/rheb in tumor cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6799808/
https://www.ncbi.nlm.nih.gov/pubmed/31637001
http://dx.doi.org/10.1038/s41392-019-0056-7
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