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Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF-Dependent Mechanism.

ABSTRACT: 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.

SUBMITTER: Thompson JM

PROVIDER: S-EPMC6072609 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF-Dependent Mechanism.

Thompson Jordan M JM Alvarez Alejandro A Singha Monika K MK Pavesic Matthew W MW Nguyen Quy H QH Nelson Luke J LJ Fruman David A DA Razorenova Olga V OV

Molecular cancer therapeutics 20180502 8

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 (<i>VHL</i>) tumor suppressor gene, which occurs in 90% of CC-RCC driving the disease. This effect has been confirmed in ...[more]

PMID: 29720560

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Project description:Breast cancer (BC) is a commonly identified life-threatening type of cancer and a major cause of death among women worldwide. Several microRNAs (miRs), including miR-143-5p, have been reported to be vital for regulating hallmarks of cancer; however, the effect of miR-143-5p on BC requires further exploration. The present study performed bioinformatics analysis on GSE42072 and GSE41922 datasets from the National Center for Biotechnology Information Gene Expression Omnibus (GEO) database to identify miR-143-5p expression patterns. Furthermore, miR-143-5p expression was detected in BC cell lines and tissues via reverse transcription-quantitative PCR. Post-transfection with miR-143-5p mimics, Cell Counting Kit-8, colony formation and Transwell assays were performed to explore the effects of miR-143-5p on BC cell proliferation, colony formation, and migration. The association of miR-143-5p with the hypoxia-inducible factor-1α (HIF-1α)-associated glucose transporter 1 (GLUT1) pathway was explored via western blotting, immunofluorescence and dual-luciferase reporter assay. The present study detected high expression of miR-143-5p in BC tissue of the GSE42072 and serum of the GSE41922 datasets by GEO chip analysis. Additionally, the expression levels of miR-143-5p were decreased in BC tissues compared with those in adjacent healthy tissues, and low miR-143-5p expression was associated with a poorer prognosis and shorter survival time in patients with BC. In vitro, miR-143-5p expression levels were decreased in BC cells, and transfection with miR-143-5p mimics suppressed BC cell proliferation, colony formation, migration. Furthermore, miR-143-5p targeted the HIF-1α-related GLUT1 pathway, and inhibited HIF-1α and GLUT1 expression. Additionally, HIF-1α agonists reversed the miR-143-5p-induced inhibition during tumorigenesis. In conclusion, miR-143-5p exhibited low expression in BC tissues, and suppressed BC cell proliferation, colony formation, migration. Moreover, the antitumor effects of miR-143-5p targeted the HIF-1α-related GLUT1 pathway.

Dataset Information

Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF-Dependent Mechanism.

Publications

Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF-Dependent Mechanism.

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