Sterol‐independent regulation of 3‐hydroxy‐3‐methylglutaryl coenzyme A reductase in tumor cells

Abstract

Elevated 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase expression supports synthesis of prenyl pyrophosphate intermediates required for tumor growth. In this study, the copy number of HMG-CoA reductase mRNA was determined in solid tumor and leukemic cell lines using competitive reverse transcriptase-polymerase chain reaction. Reductase mRNA was increased about eight-fold in Caco2 human colon adenocarcinoma cells compared with that in CCD18 normal colon cells. We also found a 50-fold enhancement of reductase mRNA in stimulated human lymphocytes compared with unstimulated cells. In CEM human leukemia cells, reductase mRNA was increased 8.6 times compared with that in stimulated lymphocytes. Greater low density lipoprotein receptor mRNA was also observed in tumor cells compared with normal counterparts. We hypothesized that elevated reductase mRNA was due to attenuation of sterol-mediated control of tumor reductase promoter activity. We first compared the methylation status of CpG dinucleotides in the promoters of reductase and p16 tumor suppressor genes from solid tumor, leukemic, and normal cells. As reported for other tumor cells the p16 promoter region was hypermethylated in Caco2 and CEM cells but was hypomethylated in corresponding normal cells. However, reductase promoter sequences in both normal and tumor cells were hypomethylated, demonstrating that methylation is not involved in sterol-independent reductase regulation. We addressed altered transcription factor binding to the tumor cell reductase promoter by transiently transfecting Caco2 and CCD18 with a plasmid vector containing a hamster HMG-CoA reductase promoter fused to the luciferase gene. We found that increased reductase mRNA was partially due to an approximately three-fold higher reductase promoter activity in Caco2 than in CCD18, measured by luciferase reporter assays. Thus, differential binding of transcription factor or factors on the tumor cell reductase promoter attenuates normal sterol-mediated regulation of reductase activity.

Cholesterol targeting alters lipid raft composition and cell survival in prostate cancer cells and xenografts

“…Cholesterol is synthesized by tumor cells but also enters cells from the circulation by LDL receptor-mediated endocytosis (24). Feedback regulation of cholesterol absorption and synthesis is lost in prostate and other types of cancer cells, resulting in upregulation of the cholesterol synthesis (mevalonate) pathway and increases in LDL receptor expression (25,26).…”

Prevention of Azoxymethane-Induced Colon Cancer by Combination of Low Doses of Atorvastatin, Aspirin, and Celecoxib in F 344 Rats

“…In human colon cancer cell lines, statins have been shown to induce apoptosis (22). Because HMG-CoA reductase, the target of statins, is overexpressed in colon cancer cell lines (23,25), its inhibition is thought to contribute to this effect. Narisawa et al (26,27) were the first to report that lovastatin and pravastatin inhibit chemically induced colon carcinogenesis in F 344 rats.…”

HMG-CoA reductase inhibitors and the malignant cell: the statin family of drugs as triggers of tumor-specific apoptosis

“…[26][27][28][29][30][31] Moreover, large retrospective analyses for drug safety and efficacy trials of statins in coronary artery disease have shown, that not only are these agents able to reduce cardiac disease-related mortality, but cancer incidence is also reduced by 28-33%. 32,33 These data further suggest these agents may have a role in cancer prophylaxis as well as therapy.…”