Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70
Abstract Although it has been established that cannabidiol (CBD), the major non-psychoactive constituent of cannabis, exerts antitumoral activities, the exact mechanism(s) via which tumor cells are killed by CBD are not well understood. This study provides new insights into the potential mechanisms...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-08-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-023-01578-9 |
| _version_ | 1797453906882592768 |
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| author | Fei Wang Ali Bashiri Dezfouli Mohammad Khosravi Wolfgang Sievert Stefan Stangl Melissa Schwab Zhiyuan Wu Katja Steiger Hu Ma Gabriele Multhoff |
| author_facet | Fei Wang Ali Bashiri Dezfouli Mohammad Khosravi Wolfgang Sievert Stefan Stangl Melissa Schwab Zhiyuan Wu Katja Steiger Hu Ma Gabriele Multhoff |
| author_sort | Fei Wang |
| collection | DOAJ |
| description | Abstract Although it has been established that cannabidiol (CBD), the major non-psychoactive constituent of cannabis, exerts antitumoral activities, the exact mechanism(s) via which tumor cells are killed by CBD are not well understood. This study provides new insights into the potential mechanisms of CBD-induced mutual antagonism of apoptosis and macroautophagy using wild type (HCT116 p53wt, LS174T p53wt), knockout (HCT116 p53−/−) and mutant (SW480 p53mut) human colorectal cancer cells (CRC). CBD causes a more pronounced loss in the viability of p53wt cells than p53−/− and p53mut cells, and a 5-week treatment with CBD reduced the volume of HCT116 p53wt xenografts in mice, but had no effect on the volume of HCT116 p53−/− tumors. Mechanistically, we demonstrate that CBD only significantly elevates ROS production in cells harboring wild-type p53 (HCT116, LS174T) and that this is associated with an accumulation of PARP1. CBD-induced elevated ROS levels trigger G0/G1 cell cycle arrest, a reduction in CDK2, a p53-dependent caspase-8/9/3 activation and macroautophagy in p53wt cells. The ROS-induced macroautophagy which promotes the activation of keap1/Nrf2 pathway might be positively regulated by p53wt, since inhibition of p53 by pifithrin-α further attenuates autophagy after CBD treatment. Interestingly, an inhibition of heat shock protein 70 (Hsp70) expression significantly enhances caspase-3 mediated programmed cell death in p53wt cells, whereas autophagy—which is associated with a nuclear translocation of Nrf2—was blocked. Taken together, our results demonstrate an intricate interplay between apoptosis and macroautophagy in CBD-treated colorectal cancer cells, which is regulated by the complex interactions of p53wt and Hsp70. |
| first_indexed | 2024-03-09T15:29:38Z |
| format | Article |
| id | doaj.art-cc7f52ea7c924210bc28ce0b5e213e37 |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-03-09T15:29:38Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-cc7f52ea7c924210bc28ce0b5e213e372023-11-26T12:21:03ZengNature Publishing GroupCell Death Discovery2058-77162023-08-019111410.1038/s41420-023-01578-9Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70Fei Wang0Ali Bashiri Dezfouli1Mohammad Khosravi2Wolfgang Sievert3Stefan Stangl4Melissa Schwab5Zhiyuan Wu6Katja Steiger7Hu Ma8Gabriele Multhoff9Radiation Immuno-Oncology Project Group, TranslaTUM—Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität MünchenRadiation Immuno-Oncology Project Group, TranslaTUM—Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität MünchenDepartment of Pathobiology, Faculty of Veterinary Medicine, Shahid Chamran University of AhvazRadiation Immuno-Oncology Project Group, TranslaTUM—Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität MünchenRadiation Immuno-Oncology Project Group, TranslaTUM—Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität MünchenRadiation Immuno-Oncology Project Group, TranslaTUM—Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität MünchenRadiation Immuno-Oncology Project Group, TranslaTUM—Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität MünchenInstitute for General Pathology and Pathological Anatomy, Technische Universität MünchenDepartment of Oncology, The Second Affiliated Hospital of Zunyi Medical UniversityRadiation Immuno-Oncology Project Group, TranslaTUM—Central Institute for Translational Cancer Research, Klinikum rechts der Isar, Technische Universität MünchenAbstract Although it has been established that cannabidiol (CBD), the major non-psychoactive constituent of cannabis, exerts antitumoral activities, the exact mechanism(s) via which tumor cells are killed by CBD are not well understood. This study provides new insights into the potential mechanisms of CBD-induced mutual antagonism of apoptosis and macroautophagy using wild type (HCT116 p53wt, LS174T p53wt), knockout (HCT116 p53−/−) and mutant (SW480 p53mut) human colorectal cancer cells (CRC). CBD causes a more pronounced loss in the viability of p53wt cells than p53−/− and p53mut cells, and a 5-week treatment with CBD reduced the volume of HCT116 p53wt xenografts in mice, but had no effect on the volume of HCT116 p53−/− tumors. Mechanistically, we demonstrate that CBD only significantly elevates ROS production in cells harboring wild-type p53 (HCT116, LS174T) and that this is associated with an accumulation of PARP1. CBD-induced elevated ROS levels trigger G0/G1 cell cycle arrest, a reduction in CDK2, a p53-dependent caspase-8/9/3 activation and macroautophagy in p53wt cells. The ROS-induced macroautophagy which promotes the activation of keap1/Nrf2 pathway might be positively regulated by p53wt, since inhibition of p53 by pifithrin-α further attenuates autophagy after CBD treatment. Interestingly, an inhibition of heat shock protein 70 (Hsp70) expression significantly enhances caspase-3 mediated programmed cell death in p53wt cells, whereas autophagy—which is associated with a nuclear translocation of Nrf2—was blocked. Taken together, our results demonstrate an intricate interplay between apoptosis and macroautophagy in CBD-treated colorectal cancer cells, which is regulated by the complex interactions of p53wt and Hsp70.https://doi.org/10.1038/s41420-023-01578-9 |
| spellingShingle | Fei Wang Ali Bashiri Dezfouli Mohammad Khosravi Wolfgang Sievert Stefan Stangl Melissa Schwab Zhiyuan Wu Katja Steiger Hu Ma Gabriele Multhoff Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70 Cell Death Discovery |
| title | Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70 |
| title_full | Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70 |
| title_fullStr | Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70 |
| title_full_unstemmed | Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70 |
| title_short | Cannabidiol-induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and Hsp70 |
| title_sort | cannabidiol induced crosstalk of apoptosis and macroautophagy in colorectal cancer cells involves p53 and hsp70 |
| url | https://doi.org/10.1038/s41420-023-01578-9 |
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