Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development
Decreasing the levels of certain proteins has been shown to be important for controlling cancer but it is currently unknown whether proteins could potentially be targeted by the inhibiting of protein synthesis. Under this circumstance, targeting protein translation could preferentially affect certai...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/7/3481 |
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| author | Saketh S. Dinavahi Yu-Chi Chen Raghavendra Gowda Pavan Kumar Dhanyamraju Kishore Punnath Dhimant Desai Arthur Berg Scot R. Kimball Shantu Amin Jin-Ming Yang Gavin P. Robertson |
| author_facet | Saketh S. Dinavahi Yu-Chi Chen Raghavendra Gowda Pavan Kumar Dhanyamraju Kishore Punnath Dhimant Desai Arthur Berg Scot R. Kimball Shantu Amin Jin-Ming Yang Gavin P. Robertson |
| author_sort | Saketh S. Dinavahi |
| collection | DOAJ |
| description | Decreasing the levels of certain proteins has been shown to be important for controlling cancer but it is currently unknown whether proteins could potentially be targeted by the inhibiting of protein synthesis. Under this circumstance, targeting protein translation could preferentially affect certain pathways, which could then be of therapeutic advantage when treating cancer. In this report, eukaryotic elongation factor-2 kinase (EEF2K), which is involved in protein translation, was shown to regulate cholesterol metabolism. Targeting EEF2K inhibited key parts of the cholesterol pathway in cancer cells, which could be rescued by the addition of exogenous cholesterol, suggesting that it is a potentially important pathway modulated by targeting this process. Specifically, targeting EEF2K significantly suppressed tumour cell growth by blocking mRNA translation of the cholesterol biosynthesis transcription factor, sterol regulatory element-binding protein (SREBP) 2, and the proteins it regulates. The process could be rescued by the addition of LDL cholesterol taken into the cells via non-receptor-mediated-uptake, which negated the need for SREBP2 protein. Thus, the levels of SREBP2 needed for cholesterol metabolism in cancer cells are therapeutically vulnerable by targeting protein translation. This is the first report to suggest that targeting EEF2K can be used to modulate cholesterol metabolism to treat cancer. |
| first_indexed | 2024-03-09T11:48:49Z |
| format | Article |
| id | doaj.art-cc14358a599a46f387267efb45fd2405 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T11:48:49Z |
| publishDate | 2022-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-cc14358a599a46f387267efb45fd24052023-11-30T23:17:31ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-03-01237348110.3390/ijms23073481Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour DevelopmentSaketh S. Dinavahi0Yu-Chi Chen1Raghavendra Gowda2Pavan Kumar Dhanyamraju3Kishore Punnath4Dhimant Desai5Arthur Berg6Scot R. Kimball7Shantu Amin8Jin-Ming Yang9Gavin P. Robertson10Department of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Public Health Sciences, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Cellular and Molecular Physiology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADepartment of Cancer Biology and Toxicology, Markey Cancer Center, College of Medicine, University of Kentucky, Lexington, KY 40536, USADepartment of Pharmacology, The Pennsylvania State University College of Medicine, Hershey, PA 17033, USADecreasing the levels of certain proteins has been shown to be important for controlling cancer but it is currently unknown whether proteins could potentially be targeted by the inhibiting of protein synthesis. Under this circumstance, targeting protein translation could preferentially affect certain pathways, which could then be of therapeutic advantage when treating cancer. In this report, eukaryotic elongation factor-2 kinase (EEF2K), which is involved in protein translation, was shown to regulate cholesterol metabolism. Targeting EEF2K inhibited key parts of the cholesterol pathway in cancer cells, which could be rescued by the addition of exogenous cholesterol, suggesting that it is a potentially important pathway modulated by targeting this process. Specifically, targeting EEF2K significantly suppressed tumour cell growth by blocking mRNA translation of the cholesterol biosynthesis transcription factor, sterol regulatory element-binding protein (SREBP) 2, and the proteins it regulates. The process could be rescued by the addition of LDL cholesterol taken into the cells via non-receptor-mediated-uptake, which negated the need for SREBP2 protein. Thus, the levels of SREBP2 needed for cholesterol metabolism in cancer cells are therapeutically vulnerable by targeting protein translation. This is the first report to suggest that targeting EEF2K can be used to modulate cholesterol metabolism to treat cancer.https://www.mdpi.com/1422-0067/23/7/3481melanomaEEF2KcholesterolSREBP2HMGCRLDLR |
| spellingShingle | Saketh S. Dinavahi Yu-Chi Chen Raghavendra Gowda Pavan Kumar Dhanyamraju Kishore Punnath Dhimant Desai Arthur Berg Scot R. Kimball Shantu Amin Jin-Ming Yang Gavin P. Robertson Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development International Journal of Molecular Sciences melanoma EEF2K cholesterol SREBP2 HMGCR LDLR |
| title | Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development |
| title_full | Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development |
| title_fullStr | Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development |
| title_full_unstemmed | Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development |
| title_short | Targeting Protein Translation in Melanoma by Inhibiting EEF-2 Kinase Regulates Cholesterol Metabolism though SREBP2 to Inhibit Tumour Development |
| title_sort | targeting protein translation in melanoma by inhibiting eef 2 kinase regulates cholesterol metabolism though srebp2 to inhibit tumour development |
| topic | melanoma EEF2K cholesterol SREBP2 HMGCR LDLR |
| url | https://www.mdpi.com/1422-0067/23/7/3481 |
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