Roles of Farnesyl-Diphosphate Farnesyltransferase 1 in Tumour and Tumour Microenvironments

Abstract

Farnesyl-diphosphate farnesyltransferase 1 (FDFT1, squalene synthase), a membrane-associated enzyme, synthesizes squalene via condensation of two molecules of farnesyl pyrophosphate. Accumulating evidence has noted that FDFT1 plays a critical role in cancer, particularly in metabolic reprogramming, cell proliferation, and invasion. Based on these advances in our knowledge, FDFT1 could be a potential target for cancer treatment. This review focuses on the contribution of FDFT1 to the hallmarks of cancer, and further, we discuss the applicability of FDFT1 as a cancer prognostic marker and target for anticancer therapy.

Keywords: cholesterol synthesis; farnesyl-diphosphate farnesyltransferase 1; lipid rafts; prognostic marker; tumour progression.

Figure 1

Biosynthesis of cholesterol and its derivatives. Squalene synthase (FDFT1) is the critical enzyme for the synthesis of sterols, and ultimately cholesterol. This enzyme plays an essential role in directing intermediates to either sterol or nonsterol branches of this metabolic pathway [60,61].

Figure 2

Role of FDFT1 in the biosynthesis of cholesterol, structure and roles of lipid rafts and regulation of FDFT1 by SREBP2. FDFT1 is the first enzyme of the cholesterol biosynthesis branch, as FDFT1 converts farnesyl pyrophosphate (FPP) into squalene which ultimately produces cholesterol and cholesterol derivatives. Therefore, inhibition of FDFT1 only impacts the cholesterol biosynthesis pathway but not an alternative pathway, where FPP is converted into other essential cellular products such as ubiquinol, dolichols, heme A, farnesylated proteins, or geranylgeranylated proteins. Cholesterol is one of the most critical components of the plasma membrane microdomain known as rafts. Beyond cholesterol, the raft is structured by transmembrane proteins, doubly acylated proteins, and glycosylphosphatidylinositol (GPI) anchored proteins. Lipid rafts contribute to a variety of cellular biological processes such as signal transduction pathways, membrane trafficking, cytoskeletal organization, synaptic transmission, apoptosis, pathogen entry, cell adhesion, and migration. One of the key transcriptions factors of FDFT1 is SREBP2. SREBP2 is located in the endoplasmic reticulum (ER) membrane as an inactive form which is bound with Insulin Induced Gene 1 (INSIG) and Sterol Regulatory Element-Binding Protein Cleavage-Activating Protein (SCAP). Upon specific signals such as cholesterol deprivation, PI3K/AKT/mTOR, hypoxia, low pH, androgens, or ER stress, SREBP2 is activated by removal of INSIG from the complex INSIG-SCAP-SREBP2, and then SCAP-SREBP2 is transported to the Golgi, where SREBP2 is cleavage by Golgi proteases to form active SREBP2. The active SREBP2 form translocates into the nucleus and binds to SRE regions in the FDFT1 promoter including sterol regulatory element (SRE)-1, Inv SRE-3, and SRE-1 (8/10), which results in transcription of FDFT1.

Figure 3

Hallmarks of cancer. Hallmarks of cancer include inappropriately sustained proliferation signals, resistance to cell death, escape from growth suppression, possible replication immortality, invasion and metastasis, inflammation promotion of cancer, avoidance of immune destruction, genetic instability and mutations, and remodelling of cellular metabolism. Seven of the cancer hallmarks originate from tumour cells themselves, while the rest are involved in the tumour microenvironments (TME).

Figure 4

The association between FDFT1 and cell death. FDFT1 is directly or indirectly associated with apoptotic signals. FDFT1 could directly activate NF-KB pathways or activate AKT through cholesterol synthesis. Activated NF-KB increases anti-apoptotic proteins, such as Bcl-xL, Bcl-2, and Bax and decreases pro-apoptotic proteins such as caspase-3, thereby blocking apoptosis signalling. In cancer cells with deficient squalene epoxidase, high expression of FDFT1 increased intracellular squalene levels, which protects the cell membrane from lipid peroxidation by ROS and further prevents the cell from entering the ferroptosis pathway. Furthermore, FDFT1 inhibition upregulates endogenous geranylgeranoic acid (GGA) content, which has been demonstrated to cause incomplete autophagy, and a decrease in cholesterol level also activates autophagy.

Figure 5

Association FDFT1 with metabolism in cancer. FDFT1 increases cholesterol in membrane microdomains, and thus traffics GLUT4 from the cytosol to lipid rafts in the cell membrane, consequently enhancing glucose uptake from TME into cells. On the other hand, FDFT1 has been determined to inhibit the Akt/mTOR/HIF-1α axis, thereby decreasing expression of glycolytic enzymes such as HK2, LDHA, PGK1, GPI, and ultimately, reducing the lactic acid concentration in the TME. However, this mechanism has only been shown in colorectal cancer [7], and it will be necessary, therefore, to determine whether FDFT1 could inhibit or activate Akt/mTOR/HIF-1α signalling in other cancers.

Figure 6

FDFT1 inhibitors. The names of the compounds corresponding to each number are shown in Table 2.