Cannabidiol alters mitochondrial bioenergetics via VDAC1 and triggers cell death in hormone-refractory prostate cancer
In spite of the huge advancements in both diagnosis and interventions, hormone refractory prostate cancer (HRPC) remains a major hurdle in prostate cancer (PCa). Metabolic reprogramming plays a key role in PCa oncogenesis and resistance. However, the dynamics between metabolism and oncogenesis are n...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Pharmacological Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1043661823000397 |
| _version_ | 1797448097633140736 |
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| author | Ali Mokhtar Mahmoud Magdalena Kostrzewa Viviana Marolda Marianna Cerasuolo Federica Maccarinelli Daniela Coltrini Sara Rezzola Arianna Giacomini Maria Pina Mollica Andrea Motta Debora Paris Antonio Zorzano Vincenzo Di Marzo Roberto Ronca Alessia Ligresti |
| author_facet | Ali Mokhtar Mahmoud Magdalena Kostrzewa Viviana Marolda Marianna Cerasuolo Federica Maccarinelli Daniela Coltrini Sara Rezzola Arianna Giacomini Maria Pina Mollica Andrea Motta Debora Paris Antonio Zorzano Vincenzo Di Marzo Roberto Ronca Alessia Ligresti |
| author_sort | Ali Mokhtar Mahmoud |
| collection | DOAJ |
| description | In spite of the huge advancements in both diagnosis and interventions, hormone refractory prostate cancer (HRPC) remains a major hurdle in prostate cancer (PCa). Metabolic reprogramming plays a key role in PCa oncogenesis and resistance. However, the dynamics between metabolism and oncogenesis are not fully understood. Here, we demonstrate that two multi-target natural products, cannabidiol (CBD) and cannabigerol (CBG), suppress HRPC development in the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model by reprogramming metabolic and oncogenic signaling. Mechanistically, CBD increases glycolytic capacity and inhibits oxidative phosphorylation in enzalutamide-resistant HRPC cells. This action of CBD originates from its effect on metabolic plasticity via modulation of VDAC1 and hexokinase II (HKII) coupling on the outer mitochondrial membrane, which leads to strong shifts of mitochondrial functions and oncogenic signaling pathways. The effect of CBG on enzalutamide-resistant HRPC cells was less pronounced than CBD and only partially attributable to its action on mitochondria. However, when optimally combined, these two cannabinoids exhibited strong anti-tumor effects in TRAMP mice, even when these had become refractory to enzalutamide, thus pointing to their therapeutical potential against PCa. |
| first_indexed | 2024-03-09T14:05:27Z |
| format | Article |
| id | doaj.art-08c7a3cef52d4ce7b7827678decc6864 |
| institution | Directory Open Access Journal |
| issn | 1096-1186 |
| language | English |
| last_indexed | 2024-03-09T14:05:27Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj.art-08c7a3cef52d4ce7b7827678decc68642023-11-30T05:05:44ZengElsevierPharmacological Research1096-11862023-03-01189106683Cannabidiol alters mitochondrial bioenergetics via VDAC1 and triggers cell death in hormone-refractory prostate cancerAli Mokhtar Mahmoud0Magdalena Kostrzewa1Viviana Marolda2Marianna Cerasuolo3Federica Maccarinelli4Daniela Coltrini5Sara Rezzola6Arianna Giacomini7Maria Pina Mollica8Andrea Motta9Debora Paris10Antonio Zorzano11Vincenzo Di Marzo12Roberto Ronca13Alessia Ligresti14National Research Council of Italy, Institute of Biomolecular Chemistry, Pozzuoli, ItalyNational Research Council of Italy, Institute of Biomolecular Chemistry, Pozzuoli, ItalyNational Research Council of Italy, Institute of Biomolecular Chemistry, Pozzuoli, ItalyUniversity of Portsmouth, School of Mathematics and Physics, Hampshire PO1 3HF, UKUniversity of Brescia, Department of Molecular and Translational Medicine, Brescia, ItalyUniversity of Brescia, Department of Molecular and Translational Medicine, Brescia, ItalyUniversity of Brescia, Department of Molecular and Translational Medicine, Brescia, ItalyUniversity of Brescia, Department of Molecular and Translational Medicine, Brescia, ItalyDepartment of Biology, University of Naples Federico II, Naples, ItalyNational Research Council of Italy, Institute of Biomolecular Chemistry, Pozzuoli, ItalyNational Research Council of Italy, Institute of Biomolecular Chemistry, Pozzuoli, ItalyInstitute for Research in Biomedicine, (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Instituto de Salud Carlos III, SpainNational Research Council of Italy, Institute of Biomolecular Chemistry, Pozzuoli, Italy; Centre de Recherche de l′Institut de Cardiologie et Pneumologie de Quebéc (CRIUCPQ) et Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Centre NUTRISS, Department of Medicine and School of Nutrition, Université Laval, Quebec City, CanadaUniversity of Brescia, Department of Molecular and Translational Medicine, Brescia, Italy; Corresponding author.National Research Council of Italy, Institute of Biomolecular Chemistry, Pozzuoli, Italy; Correspondence to: University of Brescia, viale Europa 11, 25123 Brescia, Italy.In spite of the huge advancements in both diagnosis and interventions, hormone refractory prostate cancer (HRPC) remains a major hurdle in prostate cancer (PCa). Metabolic reprogramming plays a key role in PCa oncogenesis and resistance. However, the dynamics between metabolism and oncogenesis are not fully understood. Here, we demonstrate that two multi-target natural products, cannabidiol (CBD) and cannabigerol (CBG), suppress HRPC development in the TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model by reprogramming metabolic and oncogenic signaling. Mechanistically, CBD increases glycolytic capacity and inhibits oxidative phosphorylation in enzalutamide-resistant HRPC cells. This action of CBD originates from its effect on metabolic plasticity via modulation of VDAC1 and hexokinase II (HKII) coupling on the outer mitochondrial membrane, which leads to strong shifts of mitochondrial functions and oncogenic signaling pathways. The effect of CBG on enzalutamide-resistant HRPC cells was less pronounced than CBD and only partially attributable to its action on mitochondria. However, when optimally combined, these two cannabinoids exhibited strong anti-tumor effects in TRAMP mice, even when these had become refractory to enzalutamide, thus pointing to their therapeutical potential against PCa.http://www.sciencedirect.com/science/article/pii/S1043661823000397Mitochondrial bioenergeticsCBDVDAC1Hormone refractory prostate cancerPhytocannabinoids |
| spellingShingle | Ali Mokhtar Mahmoud Magdalena Kostrzewa Viviana Marolda Marianna Cerasuolo Federica Maccarinelli Daniela Coltrini Sara Rezzola Arianna Giacomini Maria Pina Mollica Andrea Motta Debora Paris Antonio Zorzano Vincenzo Di Marzo Roberto Ronca Alessia Ligresti Cannabidiol alters mitochondrial bioenergetics via VDAC1 and triggers cell death in hormone-refractory prostate cancer Pharmacological Research Mitochondrial bioenergetics CBD VDAC1 Hormone refractory prostate cancer Phytocannabinoids |
| title | Cannabidiol alters mitochondrial bioenergetics via VDAC1 and triggers cell death in hormone-refractory prostate cancer |
| title_full | Cannabidiol alters mitochondrial bioenergetics via VDAC1 and triggers cell death in hormone-refractory prostate cancer |
| title_fullStr | Cannabidiol alters mitochondrial bioenergetics via VDAC1 and triggers cell death in hormone-refractory prostate cancer |
| title_full_unstemmed | Cannabidiol alters mitochondrial bioenergetics via VDAC1 and triggers cell death in hormone-refractory prostate cancer |
| title_short | Cannabidiol alters mitochondrial bioenergetics via VDAC1 and triggers cell death in hormone-refractory prostate cancer |
| title_sort | cannabidiol alters mitochondrial bioenergetics via vdac1 and triggers cell death in hormone refractory prostate cancer |
| topic | Mitochondrial bioenergetics CBD VDAC1 Hormone refractory prostate cancer Phytocannabinoids |
| url | http://www.sciencedirect.com/science/article/pii/S1043661823000397 |
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