Importance of mevalonate pathway lipids on the growth and survival of primary and metastatic gastric carcinoma cells

Abstract

Purpose: This preclinical study aims to determine the effect of drugs that alter isoprenoids and cholesterol metabolism in the homeostasis of gastric carcinoma cell lines in the search for new therapeutic targets for stomach cancer.

Materials and methods: Primary (AGS) and metastatic (NCI-N87) gastric cancer cell lines were treated with simvastatin and terbinafine, two inhibitors of the mevalonate pathway, and avasimibe, an inhibitor of cholesterol esterification. Cell viability and growth were measured as well as cholesterol levels and the expression of the hydroxy methyl-glutaryl CoA reductase (HMGCR) and the LDL receptor (LDLR).

Results: Primary and metastatic gastric carcinoma cells show different sensitivity to drugs that affect isoprenoid synthesis and the metabolism and uptake of cholesterol. Isoprenoids are involved in the growth and viability of both types of cells, but the role of free and esterified cholesterol for metastatic gastric cell survival is not as evident as for primary gastric cancer cells. Differential expression of LDLR due to mevalonate pathway inhibition suggests variations in the regulation of cholesterol uptake between primary and metastatic cancer cells.

Conclusion: These results indicate that at least for primary gastric cancer, statins and avasimibe are promising candidates as potential novel antitumor drugs that target the metabolism of isoprenoids and cholesterol of gastric tumors.

Purpose: This preclinical study aims to determine the effect of drugs that alter isoprenoids and cholesterol metabolism in the homeostasis of gastric carcinoma cell lines in the search for new therapeutic targets for stomach cancer. Materials and Methods: Primary (AGS) and metastatic (NCI-N87) gastric cancer cell lines were treated with simvastatin and terbinafine, two inhibitors of the mevalonate pathway, and avasimibe, an inhibitor of cholesterol esterification. Cell viability and growth were measured as well as cholesterol levels and the expression of the hydroxy methyl-glutaryl CoA reductase (HMGCR) and the LDL receptor (LDLR). Results: Primary and metastatic gastric carcinoma cells show different sensitivity to drugs that affect isoprenoid synthesis and the metabolism and uptake of cholesterol. Isoprenoids are involved in the growth and viability of both types of cells, but the role of free and esterified cholesterol for metastatic gastric cell survival is not as evident as for primary gastric cancer cells. Differential expression of LDLR due to mevalonate pathway inhibition suggests variations in the regulation of cholesterol uptake between primary and metastatic cancer cells. Conclusion: These results indicate that at least for primary gastric cancer, statins and avasimibe are promising candidates as potential novel antitumor drugs that target the metabolism of isoprenoids and cholesterol of gastric tumors.