The Mevalonate Pathway, a Metabolic Target in Cancer Therapy

Abstract

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.

Keywords: cancer; cholesterol; isoprenoids; mevalonate; oxysterols; statins; sterol regulatory element binding protein.

Figure 1

The mevalonate (MVA) pathway and its connection with the intracellular energy metabolism signaling. Diagram of the different steps of the intracellular MVA anabolic pathway, from the entry of acetyl-coenzyme A (CoA) to the production of isoprenoid metabolites. Acetyl-CoA is transformed into hydroxy-methylglutaryl-CoA (HMG-CoA) which is used by the enzyme hydroxy-methyl-glutaryl-CoA reductase (HMGCR) to synthesize MVA. MVA is further metabolized to farnesyl pyrophosphate (FPP), a precursor of cholesterol and sterols. FPP is also converted to geranylgeranyl pyrophosphate (GGPP), and these lipids are used for post-translational modification of proteins, including N-glycosylation and protein prenylation.

Figure 2

Main mechanisms involved in mevalonate (MVA) pathway dysregulation and different cancers associated. MVA pathway is upregulated in several cancers including breast, prostate, pancreatic, lung, esophageal, hepatic, and leukemia. Main mechanisms involved in the dysregulation of MVA pathway include: abnormal regulation of the enzyme hydroxy-methyl-glutaryl-CoA reductase (HMGCR) by different transcription factors such as hypoxia-inducible factor 1 (HIF-1); mutations or abnormal activation of sterol regulatory element-binding proteins (SREBPs); mutations on tumor suppressor proteins such as tumor protein (p53); decreased AMP-activated protein kinase (AMPK) activation; increased activation of signaling pathways such as phosphoinositide 3-kinase (PI3K)—protein kinase B (AKT)—mammalian target of rapamycin complex 1 (mTORC1), Janus Kinase (JAK)/Signal Transducer and Activator of Transcription 3 (STAT3) or Hippo signaling pathway (YAP-TAZ).

Figure 3

The mevalonate (MVA) pathway in cancer progression. The MVA pathway is dysregulated in several cancer cells due to mutations or abnormal signaling of different proteins/pathways. Upregulation of MVA pathway drives to increased protein prenylation thus promoting a malignant phenotype of cancer cells with an uncontrolled cell invasive growth and survival. In cancer cells expressing a mutation of tumor protein p53, there is a positive-feedback loop where p53 interacts with sterol regulatory element-binding protein (SREBP), leading to increased activation of the MVA pathway activity, and therefore higher levels of MVA. This MVA leads to the stabilization of p53 mutation as well as promotes protein prenylation, thus accelerating cancer progression.

Figure 4

Antitumoral effects of mevalonate (MVA) pathway inhibition. The inhibition of MVA pathway triggers a series of anticancer events that get to inhibit tumor growth and progression. These include the reduction of MVA synthesis, which in turn decreases the levels of downstream products (isoprenoids) and therefore prevents protein prenylation; the reduction in the translocation of small GTPases such as Rho and Ras to the cell membrane; and the inhibition of cholesterol synthesis. All these inhibitory actions suggest that targeting the MVA pathway could represent a key mechanism to prevent cancer progression.