Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF-Dependent Mechanism
| العنوان: | Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF-Dependent Mechanism |
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| المؤلفون: | Monika Singha, David A. Fruman, Matthew W. Pavesic, Alejandro Alvarez, Olga V. Razorenova, Quy H. Nguyen, Luke J. Nelson, Jordan M. Thompson |
| المصدر: | Molecular Cancer Therapeutics. 17:1781-1792 |
| بيانات النشر: | American Association for Cancer Research (AACR), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Cancer Research, Tumor suppressor gene, Mevalonic Acid, Synthetic lethality, Tumor initiation, urologic and male genital diseases, Article, 03 medical and health sciences, 0302 clinical medicine, Prenylation, medicine, Humans, Carcinoma, Renal Cell, neoplasms, Rho-associated protein kinase, Chemistry, medicine.disease, Kidney Neoplasms, female genital diseases and pregnancy complications, Gene Expression Regulation, Neoplastic, Clear cell renal cell carcinoma, 030104 developmental biology, Oncology, Von Hippel-Lindau Tumor Suppressor Protein, Cell culture, 030220 oncology & carcinogenesis, Cancer research, Mevalonate pathway, Hydroxymethylglutaryl-CoA Reductase Inhibitors |
| الوصف: | Clear cell renal cell carcinoma (CC-RCC) is a devastating disease with limited therapeutic options available for advanced stages. The objective of this study was to investigate HMG-CoA reductase inhibitors, also known as statins, as potential therapeutics for CC-RCC. Importantly, treatment with statins was found to be synthetically lethal with the loss of the von Hippel–Lindau (VHL) tumor suppressor gene, which occurs in 90% of CC-RCC driving the disease. This effect has been confirmed in three different CC-RCC cell lines with three different lipophilic statins. Inhibition of mevalonate synthesis by statins causes a profound cytostatic effect at nanomolar concentrations and becomes cytotoxic at low micromolar concentrations in VHL-deficient CC-RCC. The synthetic lethal effect can be fully rescued by both mevalonate and geranylgeranylpyrophosphate, but not by squalene, indicating that the effect is due to disruption of small GTPase isoprenylation and not the inhibition of cholesterol synthesis. Inhibition of Rho and Rho kinase (ROCK) signaling contributes to the synthetic lethality effect, and overactivation of hypoxia-inducible factor signaling resulting from VHL loss is required. Finally, statin treatment is able to inhibit both tumor initiation and progression of subcutaneous 786-OT1-based CC-RCC tumors in mice. Thus, statins represent potential therapeutics for the treatment of VHL-deficient CC-RCC. Mol Cancer Ther; 17(8); 1781–92. ©2018 AACR. |
| تدمد: | 1538-8514 1535-7163 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::267f7f7d8af06a357e6c6c4238767e31 https://doi.org/10.1158/1535-7163.mct-17-1076 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....267f7f7d8af06a357e6c6c4238767e31 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15388514 15357163 |
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