Eriodictyol mediated selective targeting of the TNFR1/FADD/TRADD axis in cancer cells induce apoptosis and inhibit tumor progression and metastasis
While the anti-inflammatory activities of Eriodictyol, a plant-derived flavonoid is well-known, reports on its anti-cancer efficacy and selective cytotoxicity in cancer cells are still emerging. However, little is known regarding its mechanism of selective anti-cancer activities. Here, we show the m...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-07-01
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| Series: | Translational Oncology |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S1936523322000924 |
| _version_ | 1818208627820855296 |
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| author | Shibjyoti Debnath Abhisek Sarkar Dipanwita Das Mukherjee Subha Ray Barun Mahata Tarun Mahata Pravat K. Parida Troyee Das Rupak Mukhopadhyay Zhumur Ghosh Kaushik Biswas |
| author_facet | Shibjyoti Debnath Abhisek Sarkar Dipanwita Das Mukherjee Subha Ray Barun Mahata Tarun Mahata Pravat K. Parida Troyee Das Rupak Mukhopadhyay Zhumur Ghosh Kaushik Biswas |
| author_sort | Shibjyoti Debnath |
| collection | DOAJ |
| description | While the anti-inflammatory activities of Eriodictyol, a plant-derived flavonoid is well-known, reports on its anti-cancer efficacy and selective cytotoxicity in cancer cells are still emerging. However, little is known regarding its mechanism of selective anti-cancer activities. Here, we show the mechanism of selective cytotoxicity of Eriodictyol towards cancer cells compared to normal cells. Investigation reveals that Eriodictyol significantly upregulates TNFR1 expression in tumor cells (HeLa and SK-RC-45) while sparing the normal cells (HEK, NKE and WI-38), which display negligible TNFR1 expression, irrespective of the absence or presence of Eriodictyol. Further investigation of the molecular events reveal that Eriodictyol induces apoptosis through expression of the pro-apoptotic DISC components leading to activation of the caspase cascade. In addition, CRISPR-Cas9 mediated knockout of TNFR1 completely blocks apoptosis in HeLa cells in response to Eriodictyol, confirming that Eriodictyol induced cancer cell apoptosis is indeed TNFR1-dependent. Finally, in vivo data demonstrates that Eriodictyol not only impedes tumor growth and progression, but also inhibits metastasis in mice implanted with 4T1 breast cancer cells. Thus, our study has identified Eriodictyol as a compound with high selectivity towards cancer cells through TNFR1 and suggests that it can be further explored for its prospect in cancer therapeutics. |
| first_indexed | 2024-12-12T04:47:50Z |
| format | Article |
| id | doaj.art-83661642592844f1a3575eddd21356dd |
| institution | Directory Open Access Journal |
| issn | 1936-5233 |
| language | English |
| last_indexed | 2024-12-12T04:47:50Z |
| publishDate | 2022-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Translational Oncology |
| spelling | doaj.art-83661642592844f1a3575eddd21356dd2022-12-22T00:37:35ZengElsevierTranslational Oncology1936-52332022-07-0121101433Eriodictyol mediated selective targeting of the TNFR1/FADD/TRADD axis in cancer cells induce apoptosis and inhibit tumor progression and metastasisShibjyoti Debnath0Abhisek Sarkar1Dipanwita Das Mukherjee2Subha Ray3Barun Mahata4Tarun Mahata5Pravat K. Parida6Troyee Das7Rupak Mukhopadhyay8Zhumur Ghosh9Kaushik Biswas10Division of Molecular Medicine, Bose Institute, Kolkata, West Bengal, 700054, IndiaDivision of Molecular Medicine, Bose Institute, Kolkata, West Bengal, 700054, IndiaDivision of Molecular Medicine, Bose Institute, Kolkata, West Bengal, 700054, IndiaDivision of Molecular Medicine, Bose Institute, Kolkata, West Bengal, 700054, IndiaDivision of Molecular Medicine, Bose Institute, Kolkata, West Bengal, 700054, IndiaDivision of Molecular Medicine, Bose Institute, Kolkata, West Bengal, 700054, IndiaDivision of Molecular Medicine, Bose Institute, Kolkata, West Bengal, 700054, IndiaThe Bioinformatics Center, Bose Institute, Kolkata, West Bengal, 700054, IndiaDepartment of Molecular Biology & Biotechnology, Tezpur University, Assam 784028The Bioinformatics Center, Bose Institute, Kolkata, West Bengal, 700054, IndiaDivision of Molecular Medicine, Bose Institute, Kolkata, West Bengal, 700054, India; Corresponding author.While the anti-inflammatory activities of Eriodictyol, a plant-derived flavonoid is well-known, reports on its anti-cancer efficacy and selective cytotoxicity in cancer cells are still emerging. However, little is known regarding its mechanism of selective anti-cancer activities. Here, we show the mechanism of selective cytotoxicity of Eriodictyol towards cancer cells compared to normal cells. Investigation reveals that Eriodictyol significantly upregulates TNFR1 expression in tumor cells (HeLa and SK-RC-45) while sparing the normal cells (HEK, NKE and WI-38), which display negligible TNFR1 expression, irrespective of the absence or presence of Eriodictyol. Further investigation of the molecular events reveal that Eriodictyol induces apoptosis through expression of the pro-apoptotic DISC components leading to activation of the caspase cascade. In addition, CRISPR-Cas9 mediated knockout of TNFR1 completely blocks apoptosis in HeLa cells in response to Eriodictyol, confirming that Eriodictyol induced cancer cell apoptosis is indeed TNFR1-dependent. Finally, in vivo data demonstrates that Eriodictyol not only impedes tumor growth and progression, but also inhibits metastasis in mice implanted with 4T1 breast cancer cells. Thus, our study has identified Eriodictyol as a compound with high selectivity towards cancer cells through TNFR1 and suggests that it can be further explored for its prospect in cancer therapeutics.http://www.sciencedirect.com/science/article/pii/S1936523322000924FlavonoidsCRISPR-Cas9Cell deathTumorigenesisSelective cytotoxicity |
| spellingShingle | Shibjyoti Debnath Abhisek Sarkar Dipanwita Das Mukherjee Subha Ray Barun Mahata Tarun Mahata Pravat K. Parida Troyee Das Rupak Mukhopadhyay Zhumur Ghosh Kaushik Biswas Eriodictyol mediated selective targeting of the TNFR1/FADD/TRADD axis in cancer cells induce apoptosis and inhibit tumor progression and metastasis Translational Oncology Flavonoids CRISPR-Cas9 Cell death Tumorigenesis Selective cytotoxicity |
| title | Eriodictyol mediated selective targeting of the TNFR1/FADD/TRADD axis in cancer cells induce apoptosis and inhibit tumor progression and metastasis |
| title_full | Eriodictyol mediated selective targeting of the TNFR1/FADD/TRADD axis in cancer cells induce apoptosis and inhibit tumor progression and metastasis |
| title_fullStr | Eriodictyol mediated selective targeting of the TNFR1/FADD/TRADD axis in cancer cells induce apoptosis and inhibit tumor progression and metastasis |
| title_full_unstemmed | Eriodictyol mediated selective targeting of the TNFR1/FADD/TRADD axis in cancer cells induce apoptosis and inhibit tumor progression and metastasis |
| title_short | Eriodictyol mediated selective targeting of the TNFR1/FADD/TRADD axis in cancer cells induce apoptosis and inhibit tumor progression and metastasis |
| title_sort | eriodictyol mediated selective targeting of the tnfr1 fadd tradd axis in cancer cells induce apoptosis and inhibit tumor progression and metastasis |
| topic | Flavonoids CRISPR-Cas9 Cell death Tumorigenesis Selective cytotoxicity |
| url | http://www.sciencedirect.com/science/article/pii/S1936523322000924 |
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