Involvement of the pro-oncogenic enzyme fatty acid synthase in the hallmarks of cancer: a promising target in anti-cancer therapies

Abstract

An accelerated de novo lipogenesis (DNL) flux is a common characteristic of cancer cells required to sustain a high proliferation rate. The DNL enzyme fatty acid synthase (FASN) is overexpressed in many cancers and is pivotal for the increased production of fatty acids. There is increasing evidences of the involvement of FASN in several hallmarks of cancer linked to its ability to promote cell proliferation via membranes biosynthesis. In this review we discuss about the implication of FASN in the resistance to cell death and in the deregulation of cellular energetics by increasing nucleic acids, protein and lipid synthesis. FASN also promotes cell proliferation, cell invasion, metastasis and angiogenesis by enabling the building of lipid rafts and consequently to the localization of oncogenic receptors such as HER2 and c-Met in membrane microdomains. Finally, FASN is involved in immune escape by repressing the activation of pro-inflammatory cells and promoting the recruitment of M2 macrophages and T regulatory cells in the tumor microenvironment. Here, we provide an overview of the involvement of the pro-oncogenic enzyme in the hallmarks of cancer making FASN a promising target in anti-cancer therapy to circumvent resistance to chemotherapies.

Fig. 1. Upregulation of FASN correlates with several hallmarks of cancer.

The pro-oncogenic enzyme FASN is involved in sustained proliferation, dysregulation of cell energetics, resistance to cell death, induction of angiogenesis, activation of invasion and metastasis, and prevention of immune destruction. Adapted from Hanahan and Weinberg, 2011 [25].

Fig. 2. FASN deregulates cell metabolism.

Many enzymes are upregulated in cancer cells including the lipogenic enzymes ACLY, ACC, and FASN. Their overexpression leads to an increased lipid synthesis sustained by the Warburg effect. In addition FASN promotes mTOR activation resulting in an increased protein synthesis. FASN also favors the activity of the PPP (pentose-phosphate pathway) enzyme PGDH by increasing the pool of NADP⁺, a co-substrate of the latter. PPP upregulation concomitantly increases DNA/RNA synthesis. The dotted arrows represent an indirect effect. PGDH, 6-phosphogluconate dehydrogenase; AcCoA, acetyl-CoA; MalCoA, malonyl-CoA; TCA, tricarboxylic acid cycle; OAA, oxaloacetic acid; ACLY, ATP citrate lyase; ACC, acetyl-CoA carboxylase; PPP, pentose-phosphate pathway; mTOR, mammalian/mechanistic target of rapamycin; FASN, fatty acid synthase.

Fig. 3. FASN promotes cell proliferation.

FASN participates in the elaboration of lipid rafts required for signaling-associated receptors including the oncogenic receptors HER2 and EGFR. Thus, a positive feedback is ON as these receptors drive FASN expression via the activation of the MAPK and PI3K/Akt/mTOR pathways. PI3K and mTOR govern the expression of the transcription factor SREBP-1 which in turn induces FASN expression. mTOR also regulates FASN mRNA translation. In addition, FASN favors indirectly EGFR palmitoylation which prevents its inhibition by TKI. Finally, FASN promotes stemness and therefore cell proliferation.

Fig. 4. FASN promotes cell migration and invasion.

FASN is phosphorylated by HER2 increasing its activity and being responsible for an activation of MMP-9 that degrades the extracellular matrix (ECM). FASN exerts a positive feedback loop by allowing HER2 localization into lipid rafts. Through a respective reduction and increase of E-cadherin and vimentin expression, FASN promotes EMT reinforced by the proper localization of the c-Met receptor into lipid rafts. FASN interacts with Src and caveolin-1. FASN indirectly participates in caveolin-1 palmitoylation which in turn promotes Src and Akt activity leading to cell migration. The dotted arrows represent an indirect effect.

Fig. 5. FASN favors angiogenesis.

The catalytic activity of FASN probably allows the localization of the oncogenic receptor VEGFR-2 in lipid rafts, a prerequisite to the regulation of angiogenesis. By producing fatty acids, FASN reduces the pool of malonyl-CoA leading to a decrease of mTOR malonylation which promotes its activity and therefore angiogenesis. FASN also controls VEGF secretion and MMP-9 activation to respectively activate VEGFR-2 and degrade the extracellular matrix (ECM), and consequently to sustain angiogenesis. The expression and activity of the transcription factor HIF-1α are positively regulated by FASN; this induces VEGF-A expression. The dotted arrows represent an indirect effect.

Fig. 6. FASN participates to immune escape.

Inhibition of FASN by orlistat induces NK cells and CD8⁺ T cells activation. Orlistat decreases the amount of T-regs whose suppressive activity is in part induced by FASN. Orlistat decreases PD-L1 expression, induces the secretion of nitric oxide (NO) by neutrophils and decreases the pool of fatty acids in dendritic cells which increases their maturation. The inhibition of FASN by C75 indirectly decreases the number of M2 macrophages but increases the pool of extracellular fatty acids that probably attract NK and CD4⁺/CD8⁺ T cells in the tumor microenvironnement. FASN is therefore involved in immune escape. The dotted arrows represent an indirect effect.