Mevalonate pathway as a novel target for the treatment of metastatic gastric cancer

Gastric mucosa tumors may present as two distinct major entities: Diffuse and intestinal subtypes. There is no standard treatment for advanced or metastatic gastric cancer. The mevalonate pathway and cholesterol homeostasis are important processes in cancer cells that may be highly relevant in terms of cell growth, survival and metastatic potential. Two model cell lines representing intestinal (NCI-N87) and diffuse (Hs746T) metastatic gastric tumor histological subtypes were treated with different drugs that alter membrane lipid metabolism to determine whether cell proliferation, viability and migration were affected. The results indicated that the cells exhibited significant differences in proliferation when treated with the cholesterol-lowering drug simvastatin, but not with terbinafine, another compound that affects cholesterol synthesis. Only simvastatin affected migration in both cell lines. Reposition studies with mevalonolactone, farnesyl pyrophosphate and geranylgeranyl pyrophosphate in the presence of high and low FBS concentrations indicated that both isoprenoids and cholesterol reversed the antiproliferative effects of simvastatin in gastric cancer cells. The cell lines used in the present study had different sensitivities to several potential anti-neoplastic agents that affect the synthesis of membrane lipids. The diffuse gastric cancer cells were particularly sensitive to simvastatin, suggesting it as an option for combination treatment.