ArticleMolecular and cellular biology2011
Therapeutic levels of the hydroxmethylglutaryl-coenzyme A reductase inhibitor lovastatin activate ras signaling via phospholipase D2.
Article in Molecular and cellular biology, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers, 1 of them a synthesis that pooled it.
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Who cites it
23 citing papers in PubMed, 1 synthesis or guideline pooled it, 44 citations in OpenAlex.
- Association between statins and clinical outcomes among men with prostate cancer: a systematic review and meta-analysis.Prostate cancer and prostatic diseases · 2016Pooled it
- MTMR regulates KRAS function by controlling plasma membrane levels of phospholipids.The Journal of cell biology · 2025Article
- The pleiotropic effects of statins: a comprehensive exploration of neurovascular unit modulation and blood-brain barrier protection.Molecular medicine (Cambridge, Mass.) · 2024Review
- Roles of small GTPases in cardiac hypertrophy (Review).Molecular medicine reports · 2024Review
- Computational Construction of Toxicant Signaling Networks.Chemical research in toxicology · 2023Article
- Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies.Biological research · 2021Review
- Ras Isoforms from Lab Benches to Lives-What Are We Missing and How Far Are We?International journal of molecular sciences · 2021Review
- Conserved statin-mediated activation of the p38-MAPK pathway protects Caenorhabditis elegans from the cholesterol-independent effects of statins.Molecular metabolism · 2020Article
- Angiotensin II, Hypercholesterolemia, and Vascular Smooth Muscle Cells: A Perfect Trio for Vascular Pathology.International journal of molecular sciences · 2020Review
- Avicin G is a potent sphingomyelinase inhibitor and blocks oncogenic K- and H-Ras signaling.Scientific reports · 2020Article
- The Pleiotropic Effects of Statins - From Coronary Artery Disease and Stroke to Atrial Fibrillation and Ventricular Tachyarrhythmia.Current vascular pharmacology · 2019Review
- Insights from Second-Line Treatments for Idiopathic Dilated Cardiomyopathy.Journal of cardiovascular development and disease · 2017Article
- Mechanisms underlying cognitive deficits in a mouse model for Costello Syndrome are distinct from other RASopathy mouse models.Scientific reports · 2017Article
- Pleiotropic Effects of Statins on the Cardiovascular System.Circulation research · 2017Review
- Lovastatin lowers the risk of breast cancer: a population-based study using logistic regression with a random effects model.SpringerPlus · 2016Article
- Lovastatin-Mediated Changes in Human Tendon Cells.Journal of cellular physiology · 2015Article
- Targeting RAS Membrane Association: Back to the Future for Anti-RAS Drug Discovery?Clinical cancer research : an official journal of the American Association for Cancer Research · 2015Review
- Statins Increase Plasminogen Activator Inhibitor Type 1 Gene Transcription through a Pregnane X Receptor Regulated Element.PloS one · 2015Article
- A review of statin use and prostate cancer.Current atherosclerosis reports · 2015Review
- Lipin-1 regulates autophagy clearance and intersects with statin drug effects in skeletal muscle.Cell metabolism · 2014Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Hydroxmethylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitors (statins) lower serum cholesterol but exhibit pleiotropic biological effects that are difficult to ascribe solely to cholesterol depletion. Here, we investigated the effect of lovastatin on protein prenylation and cell signaling. We show that high concentrations (50 μM) of lovastatin inhibit Ras, Rho, and Rap prenylation but that therapeutic levels of lovastatin (50 nM to 500 nM) do not. In contrast, depletion of cellular cholesterol by therapeutic levels of lovastatin increased Ras GTP loading and mitogen-activated protein kinase (MAPK) activation in human umbilical vein endothelial cells and rodent fibroblasts. Elevated Ras signaling was not seen in statin-treated cells if cholesterol levels were maintained by supplementation. Activation of Ras-MAPK signaling was a consequence of, and dependent on, activation of phospholipase D2 (PLD2). Expression of dominant interfering PLD2 or biochemical inhibition of PLD2 abrogated Ras and MAPK activation induced by lovastatin. In contrast, ectopic expression of wild-type PLD2 enhanced Ras and MAPK activation in response to therapeutic levels of lovastatin. Statin-induced cholesterol depletion also modestly activated the epidermal growth factor receptor (EGFR), resulting in downregulation of EGFR expression. These results suggest that statins modulate key cell signaling pathways as a direct consequence of cholesterol depletion and identify the EGFR-PLD2-Ras-MAPK axis as an important statin target.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.