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

被引:62
作者
Hentosh, P
Yuh, SH
Elson, CE
Peffley, DM
机构
[1] Univ Hlth Sci, Dept Pharmacol, Kansas City, MO USA
[2] Finch Univ Hlth Sci Chicago Med Sch, Dept Mol & Cellular Pharmacol, N Chicago, IL 60064 USA
[3] Univ Wisconsin, Dept Nutr Sci, Madison, WI 53706 USA
[4] Univ Hlth Sci, Dept Biochem, Kansas City, MO 64106 USA
关键词
mRNA; nonsterol transcriptional regulation; isoprenoid synthesis; signal transduction;
D O I
10.1002/mc.1074
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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. (C) 2001 Wiley-Liss, Inc.
引用
收藏
页码:154 / 166
页数:13
相关论文
共 57 条
[1]   Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac [J].
Agarwal, B ;
Rao, CV ;
Bhendwal, S ;
Ramey, WR ;
Shirin, H ;
Reddy, BS ;
Holt, PR .
GASTROENTEROLOGY, 1999, 117 (04) :838-847
[2]   Tyrosine kinase-dependent modulation of 3-hydroxy-3-methylglutaryl-CoA reductase in human breast adenocarcinoma SKBR-3 cells [J].
Asslan, R ;
Pradines, A ;
Favre, G ;
Le Gaillard, F .
BIOCHEMICAL JOURNAL, 1998, 330 :241-246
[3]   Epidermal growth factor stimulates 3-hydroxy-3-methylglutaryl-coenzyme A reductase expression via the ErbB-2 pathway in human breast adenocarcinoma cells [J].
Asslan, R ;
Pradines, A ;
Pratx, C ;
Allal, C ;
Favre, G ;
Le Gaillard, F .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1999, 260 (03) :699-706
[4]   REGULATION OF THE LOW-DENSITY LIPOPROTEIN RECEPTOR AND HYDROXYMETHYLGLUTARYL COENZYME-A REDUCTASE GENES BY PROTEIN KINASE-C AND A PUTATIVE NEGATIVE REGULATORY PROTEIN [J].
AUWERX, JH ;
CHAIT, A ;
DEEB, SS .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (04) :1133-1137
[5]   Nutrient regulation of gene expression by the sterol regulatory element binding proteins:: Increased recruitment of gene-specific coregulatory factors and selective hyperacetylation of histone H3 in vivo [J].
Bennett, MK ;
Osborne, TF .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2000, 97 (12) :6340-6344
[6]   The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor [J].
Brown, MS ;
Goldstein, JL .
CELL, 1997, 89 (03) :331-340
[7]   INVITRO METHYLATION OF CPG-RICH ISLANDS [J].
CAROTTI, D ;
PALITTI, F ;
LAVIA, P ;
STROM, R .
NUCLEIC ACIDS RESEARCH, 1989, 17 (22) :9219-9229
[8]   INHIBITION OF PROTEIN-SYNTHESIS IN BABY-HAMSTER KIDNEY-CELLS BLOCKS OXYSTEROL-MEDIATED SUPPRESSION OF 3-HYDROXY-3-METHYLGLUTARYL-COA REDUCTASE MESSENGER-RNA AT A POSTTRANSCRIPTIONAL LEVEL [J].
CHOI, JW ;
LUNDQUIST, EN ;
PEFFLEY, DM .
BIOCHEMICAL JOURNAL, 1993, 296 :859-866
[9]   Role of cholesterol synthesis and esterification in the growth of CEM and MOLT4 lymphoblastic cells [J].
Dessi, S ;
BAtetta, B ;
Pani, A ;
Spano, O ;
Sanna, F ;
Putzolu, M ;
Bonatesta, R ;
Piras, S ;
Pani, P .
BIOCHEMICAL JOURNAL, 1997, 321 :603-608
[10]   Increased sensitivity of acute myeloid leukemias to lovastatin-induced apoptosis: A potential therapeutic approach [J].
Dimitroulakos, J ;
Nohynek, D ;
Backway, KL ;
Hedley, DW ;
Yeger, H ;
Freedman, MH ;
Minden, MD ;
Penn, LZ .
BLOOD, 1999, 93 (04) :1308-1318