Activation of the cholesterol pathway and Ras maturation in response to stress.
All cells depend on sterols and isoprenoids derived from mevalonate (MVA) for growth, differentiation, and maintenance of homeostatic functions. In plants, environmental insults like heat and sunlight trigger the synthesis of isoprene, also derived from MVA, and this phenomenon has been associated with enhanced tolerance to heat. Here, we show that in human prostate adenocarcinoma PC-3M cells heat shock leads to activation of the MVA pathway. This is characterized by a dose- and time-dependent elevation in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) activity, enhanced sterol and isoprenoid synthesis, and increased protein prenylation. Furthermore, prenylation and subsequent membrane localization of Ras, a central player in cell signaling, was rapidly induced following heat stress. These effects were dose-dependent, augmented with repeated insults, and were prevented by culturing cells in the presence of lovastatin, a competitive inhibitor of HMGR. Enhanced Ras maturation by heat stress was also associated with a heightened activation of extracellular signal-regulated kinase (ERK), a key mediator of both mitogenic and stress signaling pathways, in response to subsequent growth factor stimulation. Thus, activation of the MVA pathway may constitute an important adaptive host response to stress, and have significant implications to carcinogenesis.
Shack
S
S
Cell Stress and Aging Section, Laboratory of Biological Chemistry, National Institute on Aging, NIH, 5600 Nathan Shock Drive, Baltimore, Maryland, MD 21224, USA.
Gorospe
M
M
Fawcett
T W
TW
Hudgins
W R
WR
Holbrook
N J
NJ
D000230:Adenocarcinoma / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D004224:Diterpenes / Q000378:metabolism; D005204:Farnesol / Q000378:metabolism; D011905:Genes, ras; D018869:Heat-Shock Response / Q000235:genetics; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D008148:Lovastatin / Q000494:pharmacology; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D017368:Protein Prenylation; D013261:Sterols / Q000096:biosynthesis; D013312:Stress, Physiological / Q000150:complications / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
D004224:Diterpenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013261:Sterols; D005204:Farnesol; D002784:Cholesterol; D008148:Lovastatin; C017338:geranylgeraniol; D006903:Hydroxymethylglutaryl CoA Reductases; D025782:Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins; D008798:Mevalonic Acid