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Exploiting the Metabolic Consequences of PTEN Loss and Akt/Hexokinase 2 Hyperactivation in Prostate Cancer: A New Role for δ-Tocotrienol
The Warburg effect is commonly recognized as a hallmark of nearly all tumors. In prostate cancer (PCa), it has been shown to be driven by PTEN loss- and Akt hyperactivation-associated upregulation of hexokinase 2 (HK2). δ-Tocotrienol (δ-TT) is an extensively studied antitumor compound; however, its...
Autores principales: | , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103956/ https://www.ncbi.nlm.nih.gov/pubmed/35563663 http://dx.doi.org/10.3390/ijms23095269 |
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author | Fontana, Fabrizio Anselmi, Martina Limonta, Patrizia |
author_facet | Fontana, Fabrizio Anselmi, Martina Limonta, Patrizia |
author_sort | Fontana, Fabrizio |
collection | PubMed |
description | The Warburg effect is commonly recognized as a hallmark of nearly all tumors. In prostate cancer (PCa), it has been shown to be driven by PTEN loss- and Akt hyperactivation-associated upregulation of hexokinase 2 (HK2). δ-Tocotrienol (δ-TT) is an extensively studied antitumor compound; however, its role in affecting PCa glycolysis is still unclear. Herein, we demonstrated that δ-TT inhibits glucose uptake and lactate production in PTEN-deficient LNCaP and PC3 PCa cells, by specifically decreasing HK2 expression. Notably, this was accompanied by the inhibition of the Akt pathway. Moreover, the nutraceutical could synergize with the well-known hypoglycemic agent metformin in inducing PCa cell death, highlighting the crucial role of the above metabolic phenotype in δ-TT-mediated cytotoxicity. Collectively, these results unravel novel inhibitory effects of δ-TT on glycolytic reprogramming in PCa, thus providing new perspectives into the mechanisms of its antitumor activity and into its use in combination therapy. |
format | Online Article Text |
id | pubmed-9103956 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-91039562022-05-14 Exploiting the Metabolic Consequences of PTEN Loss and Akt/Hexokinase 2 Hyperactivation in Prostate Cancer: A New Role for δ-Tocotrienol Fontana, Fabrizio Anselmi, Martina Limonta, Patrizia Int J Mol Sci Article The Warburg effect is commonly recognized as a hallmark of nearly all tumors. In prostate cancer (PCa), it has been shown to be driven by PTEN loss- and Akt hyperactivation-associated upregulation of hexokinase 2 (HK2). δ-Tocotrienol (δ-TT) is an extensively studied antitumor compound; however, its role in affecting PCa glycolysis is still unclear. Herein, we demonstrated that δ-TT inhibits glucose uptake and lactate production in PTEN-deficient LNCaP and PC3 PCa cells, by specifically decreasing HK2 expression. Notably, this was accompanied by the inhibition of the Akt pathway. Moreover, the nutraceutical could synergize with the well-known hypoglycemic agent metformin in inducing PCa cell death, highlighting the crucial role of the above metabolic phenotype in δ-TT-mediated cytotoxicity. Collectively, these results unravel novel inhibitory effects of δ-TT on glycolytic reprogramming in PCa, thus providing new perspectives into the mechanisms of its antitumor activity and into its use in combination therapy. MDPI 2022-05-09 /pmc/articles/PMC9103956/ /pubmed/35563663 http://dx.doi.org/10.3390/ijms23095269 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 Fontana, Fabrizio Anselmi, Martina Limonta, Patrizia Exploiting the Metabolic Consequences of PTEN Loss and Akt/Hexokinase 2 Hyperactivation in Prostate Cancer: A New Role for δ-Tocotrienol |
title | Exploiting the Metabolic Consequences of PTEN Loss and Akt/Hexokinase 2 Hyperactivation in Prostate Cancer: A New Role for δ-Tocotrienol |
title_full | Exploiting the Metabolic Consequences of PTEN Loss and Akt/Hexokinase 2 Hyperactivation in Prostate Cancer: A New Role for δ-Tocotrienol |
title_fullStr | Exploiting the Metabolic Consequences of PTEN Loss and Akt/Hexokinase 2 Hyperactivation in Prostate Cancer: A New Role for δ-Tocotrienol |
title_full_unstemmed | Exploiting the Metabolic Consequences of PTEN Loss and Akt/Hexokinase 2 Hyperactivation in Prostate Cancer: A New Role for δ-Tocotrienol |
title_short | Exploiting the Metabolic Consequences of PTEN Loss and Akt/Hexokinase 2 Hyperactivation in Prostate Cancer: A New Role for δ-Tocotrienol |
title_sort | exploiting the metabolic consequences of pten loss and akt/hexokinase 2 hyperactivation in prostate cancer: a new role for δ-tocotrienol |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9103956/ https://www.ncbi.nlm.nih.gov/pubmed/35563663 http://dx.doi.org/10.3390/ijms23095269 |
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