Therapeutic levels of the hydroxmethylglutaryl-coenzyme A reductase inhibitor lovastatin activate ras signaling via phospholipase D2.
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.
Department of Integrative Biology and Pharmacology, The University of Texas Medical School-Houston, 6431 Fannin Street, Houston, TX 77030, USA.
Kwang-Jin
KJ
Cho
Michelle M
MM
Hill
Sravanthi
S
Chigurupati
Guangwei
G
Du
Robert G
RG
Parton
John F
JF
Hancock
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002460:Cell Line; D002784:Cholesterol / Q000378:metabolism; D006224:Cricetinae; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008148:Lovastatin / Q000494:pharmacology* / Q000627:therapeutic use; D010739:Phospholipase D / Q000378:metabolism*; D017368:Protein Prenylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D018631:ras Proteins / Q000378:metabolism*; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000924:Anticholesteremic Agents; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D002784:Cholesterol; D008148:Lovastatin; D066246:ErbB Receptors; C105606:phospholipase D2; D010739:Phospholipase D; D018631:ras Proteins; D020741:rho GTP-Binding Proteins
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