Certain colon tumor hepatic metastases exhibit a deficiency of LDL receptors (LDL-R); additionally, colon tumor cell lines, unlike normal fibroblasts or hepatocytes, are unable to reverse a mevinolin imposed inhibition of HMGCoA reductase (HMGCoA-R) in the presence of LDL. Receptor deficiency could lead to, or result from, an enhanced activity of HMGCoA- R, the key enzyme regulating synthesis of mevalonate and its derivatives. Due to the central role mevalonate metabolism plays in mammalian cells, higher endogenous concentrations of the constituents of this pathway could affect the degree to which the ras protein is incorporated into the plasma membrane, potentially permitting a higher degree of ras activity in such colonic tumors. Thus an enhancement of ras activation is potentially a selective force in the development of colon cancers that may lead to a deficiency in LDL-R expression, or an uncoupling of this pathway to cellular growth needs. The magnitude of the dysregulation of the reductase and its potential effect on the expression of the product of the ras oncogene will be determined to examine the etiologic importance of these changes in the development of certain colon cancers. The response of the cells to either mevinolin inhibition of Reductase, or growth in the presence of exogenous sterols as LDL, will be assessed in vitro and in vivo in regard to: 1) HMGCoA-R activity, and 2)transcription of the LDL-R and HMGCoA-R genes. The role of mevinolin treatment in anchorage independent growth in vitro in relation to the ras protein's: 1)isoprenylation 2) membrane association and 3) activity, will be evaluated. The ability of mevinolin treatment to affect the expression of the ras protein in vivo will be determined using tumors implanted into the hepatic site of nude mice. Intrasplenic inoculations of the tumors will be accomplished as an assessment of the impact of mevinolin treatment (ras isoprenylation) upon the metastatic propensity of the tumors in vivo. The impact of exogenously supplied human LDL upon mevinolins action will be determined. The significance of dysregulations of this pathway which can lead to or be caused by LDL-R deficiency or loss will be evaluated in human colonic tissues ranging from adenomas to carcinoma in situ and hepatic metastases by IgGC-7 staining for LDL-R, northern blot for both LDL-R and HMGCoA-R gene expression, and concurrent analysis of the membrane expression and transformed character of cellular ras genes by FITC and PCR techniques. An understanding of the control of the mevalonate pathway in colon tumors may provide a cohesive theory incorporating the proliferative response in normal and transformed colonic mucosal cells in relation to loss of LDL-R function, subsequent dysregulation of the mevalonate/cholesterol biosynthetic pathway, farnesylation of the ras protein, and the oncogenic process.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Metabolic Pathology Study Section (MEP)
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Boston University
Schools of Medicine
United States
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