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

ABSTRACT: 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.

SUBMITTER: Ortiz N

PROVIDER: S-EPMC7573883 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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

Ortiz Natalia N Díaz Cecilia C

Oncology letters 20201001 6

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 differe ...[more]

PMID: 33093924

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Project description:A hallmark of cancer cells includes a metabolic reprograming that provides energy, the essential building blocks, and signaling required to maintain survival, rapid growth, metastasis, and drug resistance of many cancers. The influence of tumor microenviroment on cancer cells also results an essential driving force for cancer progression and drug resistance. Lipid-related enzymes, lipid-derived metabolites and/or signaling pathways linked to critical regulators of lipid metabolism can influence gene expression and chromatin remodeling, cellular differentiation, stress response pathways, or tumor microenviroment, and, collectively, drive tumor development. Reprograming of lipid metabolism includes a deregulated activity of mevalonate (MVA)/cholesterol biosynthetic pathway in specific cancer cells which, in comparison with normal cell counterparts, are dependent of the continuous availability of MVA/cholesterol-derived metabolites (i.e., sterols and non-sterol intermediates) for tumor development. Accordingly, there are increasing amount of data, from preclinical and epidemiological studies, that support an inverse association between the use of statins, potent inhibitors of MVA biosynthetic pathway, and mortality rate in specific cancers (e.g., colon, prostate, liver, breast, hematological malignances). In contrast, despite the tolerance and therapeutic efficacy shown by statins in cardiovascular disease, cancer treatment demands the use of relatively high doses of single statins for a prolonged period, thereby limiting this therapeutic strategy due to adverse effects. Clinically relevant, synergistic effects of tolerable doses of statins with conventional chemotherapy might enhance efficacy with lower doses of each drug and, probably, reduce adverse effects and resistance. In spite of that, clinical trials to identify combinatory therapies that improve therapeutic window are still a challenge. In the present review, we revisit molecular evidences showing that deregulated activity of MVA biosynthetic pathway has an essential role in oncogenesis and drug resistance, and the potential use of MVA pathway inhibitors to improve therapeutic window in cancer.

Dataset Information

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

Publications

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

Similar Datasets

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