Inhibition of de novo Palmitate Synthesis by Fatty Acid Synthase Induces Apoptosis in Tumor Cells by Remodeling Cell Membranes, Inhibiting Signaling Pathways, and Reprogramming Gene Expression

Abstract

Inhibition of de novo palmitate synthesis via fatty acid synthase (FASN) inhibition provides an unproven approach to cancer therapy with a strong biological rationale. FASN expression increases with tumor progression and associates with chemoresistance, tumor metastasis, and diminished patient survival in numerous tumor types. TVB-3166, an orally-available, reversible, potent, and selective FASN inhibitor induces apoptosis, inhibits anchorage-independent cell growth under lipid-rich conditions, and inhibits in-vivo xenograft tumor growth. Dose-dependent effects are observed between 20–200 nM TVB-3166, which agrees with the IC50 in biochemical FASN and cellular palmitate synthesis assays. Mechanistic studies show that FASN inhibition disrupts lipid raft architecture, inhibits biological pathways such as lipid biosynthesis, PI3K–AKT–mTOR and β-catenin signal transduction, and inhibits expression of oncogenic effectors such as c-Myc; effects that are tumor-cell specific. Our results demonstrate that FASN inhibition has anti-tumor activities in biologically diverse preclinical tumor models and provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers, including those expressing mutant K-Ras, ErbB2, c-Met, and PTEN. The reported findings inform ongoing studies to link mechanisms of action with defined tumor types and advance the discovery of biomarkers supporting development of FASN inhibitors as cancer therapeutics.Research in contextFatty acid synthase (FASN) is a vital enzyme in tumor cell biology; the over-expression of FASN is associated with diminished patient prognosis and resistance to many cancer therapies. Our data demonstrate that selective and potent FASN inhibition with TVB-3166 leads to selective death of tumor cells, without significant effect on normal cells, and inhibits in vivo xenograft tumor growth at well-tolerated doses. Candidate biomarkers for selecting tumors highly sensitive to FASN inhibition are identified. These preclinical data provide mechanistic and pharmacologic evidence that FASN inhibition presents a promising therapeutic strategy for treating a variety of cancers.

(−)-UB006: A new fatty acid synthase inhibitor and cytotoxic agent without anorexic side effects

“…(-)-UB006 and (+)-UB006, at 2 µg/ mL concentration, produced an 85% and 68% reduction in fatty acid synthesis 13 activity respectively (Fig. 8 Our data agree with those of studies on other FAS inhibitors [25] of lipid biosynthesis, which deplete the palmitate and palmitate-derived lipids required in multiple cellular processes for tumour cell growth, proliferation and survival.…”

“…It has been described that FAS inhibitors trigger cell death by apoptotic mechanisms [25,26]. In an attempt to elucidate the mechanism of action of (-)-UB006, we first measured the mRNA expression of apoptotic-marker caspase-3 and ER stress chaperone BiP or energy stress factor DDIT4/REDD1 [27] (Fig.…”

Molecular Pathways: Fatty Acid Synthase

“…FASN inhibition not only can reduce this important posttranslation modification of these proteins, but also may have more specific effects on the activation of b-catenin alone. By disrupting the classical Wnt/ b-catenin pathway, expression of important tumor survival proteins such as c-MYC can be significantly reduced (22).…”

De Novo Palmitate Synthesis Supports Oncogenic Signalling and Tumor Growth Through Diverse Mechanisms: Implications for FASN-Targeted Therapeutics

“…Constitutive or inappropriate activation of biological signalling pathways regulating cell growth, proliferation, and survival is a wellrecognized hallmark of cancer initiation and progression [1][2][3][4][5]. Deregulation and reprogramming of cellular metabolism has been recognized as an additional hallmark [5,6].…”

“…Many additional proteins are acetylated with a variety of lipid-associated moieties including GPI, farnesyl, acetate, and myristate. Thus, it is clear that post-translational acylation provides a vital mechanism to regulate cell growth, proliferation, and survival, and accordingly, some of the enzymes that catalyze synthesis and transfer of lipid and acyl groups deserve serious consideration as potential targets for the discovery and development of cancer therapeutics, for example, palmitoyl transferases [3]. Farnesyl transferase inhibitors have not demonstrated clinical efficacy due to the ability of geranylation to substitute for the farnesyl group on proteins such as Ras [36,37]; however, palmitoyl transferases are not expected to suffer from this mechanism of resistance.…”