Treatment with lovastatin, cholestyramine or niacin alters K-ras membrane association in mouse lung in a strain-dependent manner: results in females.
Hypocholesterolemic drugs may themselves increase (cholestyramine, CS) or decrease (lovastatin, Lov) peripheral tissue de novo cholesterol biosynthesis. This will alter the abundance of prenyl groups and potentially increase (CS) or decrease (Lov) K-ras membrane localization, with possible pro- or anti-carcinogenic effects (K-ras is a proto-oncogene frequently mutated in lung cancer). Female A/J, Swiss, and C57BL/6 mice were fed 2 or 4% CS, 1% niacin, or injected with Lov three (Lov-3x) or five (Lov-5x) times per week. After three weeks, serum cholesterol and triglycerides were determined enzymatically. Total, membrane, and cytoplasmic K-ras proteins were determined in lung homogenates by immunoprecipitation followed by Western blotting with a K-ras specific antibody. CS feeding increased membrane K-ras as hypothesized in A/J and C57BL/6 mice, but had no effect in Swiss mice. Lov failed in all three strains to reduce membrane K-ras, and resulted in an increase in total K-ras in A/J and C57BL/6 mice, while again lacking effect in Swiss mice. Niacin had no effect on K-ras protein in any mouse strain. These results differ from our published results for male mice of the same strains, particularly for A/J mice. Increased amounts of K-ras protein in the membrane fraction of A/J females (but not males) treated with either Lov or CS imply that if K-ras were to become mutated, CS could result in increased lung tumorigenesis and Lov would be less likely to be protective in females. In the light of these data, both sexes should be included in future animal and human chemoprevention trials.
Calvert
Richard J
RJ
Division of Research and Applied Technology, Office of Nutritional Products, Labeling and Dietary Supplements, Center for Food Safety and Applied Nutrition, US Food and Drug Administration, College Park, MD 20740, USA. calvert@mail.ncifcrf.gov
Tepper
Shirley
S
Diwan
Bhalchandra A
BA
Anderson
Lucy M
LM
Kritchevsky
David
D
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002792:Cholestyramine Resin / Q000494:pharmacology*; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008055:Lipids / Q000097:blood; D008148:Lovastatin / Q000494:pharmacology*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009525:Niacin / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D012737:Sex Factors; D018631:ras Proteins / Q000378:metabolism*
D000924:Anticholesteremic Agents; D008055:Lipids; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D002792:Cholestyramine Resin; D009525:Niacin; D008148:Lovastatin; D018631:ras Proteins