Anticancer properties of the fatty acid synthase inhibitor TVB-3166 on oral squamous cell carcinoma cell lines

Aquino, Iara Gonçalves; Bastos, Débora Campanella; Zelaya, Florence Juana María Cuadra; Teixeira, Isadora Ferrari; Salo, Tuula; Coletta, Ricardo D.; Graner, Edgard

doi:10.1016/j.archoralbio.2020.104707

Cited by 21 publications

(16 citation statements)

References 43 publications

(70 reference statements)

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“…G28UCM belong to a group of novel drugs that strongly bind to the b-ketoacyl reductase (KR) domain of FASN and act via similar molecular mechanisms. They show equivalent on-target effects and inhibit the in vitro and in vivo growth of OC and many other solid tumors with IC 50 concentrations in the µM range (32)(33)(34)(35). Interestingly, despite these similarities, treated OC cells, unlike colorectal cancer cells, showed neither CD36 upregulation nor activation of lipid uptake.…”

Section: Discussionmentioning

confidence: 99%

The Pharmacological or Genetic Blockade of Endogenous De Novo Fatty Acid Synthesis Does Not Increase the Uptake of Exogenous Lipids in Ovarian Cancer Cells

et al. 2021

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Ovarian cancer(OC) is a serious threat to women worldwide. Peritoneal dissemination, ascites and omental metastasis are typical features for disease progression, which occurs in a micro-environment that is rich in high-energy lipids. OC cells require high amounts of lipids for survival and growth. Not only do they import lipids from the host, they also produce lipids de novo. Inhibitors of fatty acid(FA) synthase(FASN) – the rate-limiting enzyme of endogenous FA synthesis that is overexpressed in OC – induce growth-arrest and apoptosis, rendering them promising candidates for cancer drug development. However, cancer researchers have long hypothesized that the lipid deficiency caused by FASN inhibition can be circumvented by increasing the uptake of exogenous lipids from the host, which would confer resistance to FASN inhibitors. In contrast to a very recent report in colorectal cancer, we demonstrate in OC cells (A2780, OVCAR3, SKOV3) that neither FASN inhibitors (G28UCM, Fasnall) nor FASN-specific siRNAs can stimulate a relief pathway leading to enhanced uptake of extrinsic FAs or low density lipoproteins (LDLs). Instead, we observed that the growth-arrest due to FASN inhibition or FASN knock-down was associated with significant dose- and time-dependent reduction in the uptake of fluorescently labeled FAs and LDLs. Western blotting showed that the expression of the FA receptor CD36, the LDL receptor(LDLR) and the lipid transport proteins fatty acid binding proteins 1–9 (FABP1–9) was not affected by the treatment. Next, we compared experimental blockade of endogenous lipid production with physiologic depletion of exogenous lipids. Lipid-free media, similar to FASN inhibitors, caused growth-arrest. Although lipid-depleted cells have diminished amounts of CD36, LDLR and FABPs, they can still activate a restorative pathway that causes enhanced import of fluorophore-labeled FAs and LDLs. Overall, our data show that OC cells are strictly lipid-depend and exquisitely sensitive to FASN inhibitors, providing a strong rationale for developing anti-FASN strategies for clinical use against OC.

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Section: Discussionmentioning

confidence: 99%

The Pharmacological or Genetic Blockade of Endogenous De Novo Fatty Acid Synthesis Does Not Increase the Uptake of Exogenous Lipids in Ovarian Cancer Cells

et al. 2021

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“…FASN activity is required for replication of several enveloped viruses, including Chikungunya, 10 HIV-1, 9 Influenza, 42 and SARS-CoV-2, 43 and many others. 6,7,13 FASN inhibitors, including Fasnall 9,35 and the TVB compounds 44,45 have therapeutic potential, and pharmacological inhibition of FASN has been shown to modulate fatty acylation of viral proteins, including Chikungunya virus nsP1 palmitoylation, 46 SARS-CoV-2 spike palmitoylation, 43 and HIV-1 Gag myristoylation (Figure 3). In other cases, modulation of FASN activity affects host proteins that regulate infection, including MYD88 palmitoylation, 47 and the results presented here that reveal that FASN activity is required for an effective IFNβ immune response against influenza virus, possibly by providing fatty acyl moieties for modification of IFITM3.…”

Section: Discussionmentioning

confidence: 99%

A bioorthogonal chemical reporter for fatty acid synthase-dependent protein acylation

Karthigeyan

Zhang

Loiselle

et al. 2021

Preprint

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Cells acquire fatty acids from dietary sources or via de novo palmitate production by fatty acid synthase (FASN). Although most cells express FASN at low levels, it is upregulated in cancers and during replication of many viruses. The precise role of FASN in disease pathogenesis is poorly understood, and whether de novo fatty acid synthesis contributes to host or viral protein acylation has been traditionally difficult to study. We describe a cell permeable, click-chemistry compatible alkynyl-acetate analog (Alk-4) that functions as a reporter of FASN-dependent protein acylation. In a FASN-dependent manner, Alk-4 selectively labeled the cellular protein interferon-induced transmembrane protein 3 (IFITM3) at its palmitoylation sites, and the HIV-1 matrix protein at its myristoylation site. Alk-4 metabolic labeling also enabled biotin-based purification and identification of more than 200 FASN-dependent acylated cellular proteins. Thus, Alk-4 is a useful bioorthogonal tool to selectively probe FASN-mediated protein acylation in normal and diseased states.

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“…FASN activity is required for replication of several enveloped viruses, including chikungunya ( 10 ), HIV-1 ( 9 ), influenza ( 43 ), severe acute respiratory syndrome coronavirus 2 ( 44 ), and many others ( 6 , 7 , 13 ). FASN inhibitors, including Fasnall ( 9 , 36 ) and the TVB compounds ( 45 , 46 ), have therapeutic potential, and pharmacological inhibition of FASN has been shown to modulate fatty acylation of viral proteins, including chikungunya virus nsP1 palmitoylation ( 11 ), severe acute respiratory syndrome coronavirus 2 spike palmitoylation ( 44 ), and HIV-1 Gag myristoylation ( Fig. 3 ).…”

Section: Discussionmentioning

confidence: 99%

A bioorthogonal chemical reporter for fatty acid synthase–dependent protein acylation

Karthigeyan

Zhang

Loiselle

et al. 2021

Journal of Biological Chemistry

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Anticancer properties of the fatty acid synthase inhibitor TVB-3166 on oral squamous cell carcinoma cell lines

Abstract: Anticancer properties of the fatty acid synthase inhibitor TVB-3166 on oral squamous cell carcinoma cell lines

Cited by 21 publications

References 43 publications

The Pharmacological or Genetic Blockade of Endogenous De Novo Fatty Acid Synthesis Does Not Increase the Uptake of Exogenous Lipids in Ovarian Cancer Cells

The Pharmacological or Genetic Blockade of Endogenous De Novo Fatty Acid Synthesis Does Not Increase the Uptake of Exogenous Lipids in Ovarian Cancer Cells

A bioorthogonal chemical reporter for fatty acid synthase-dependent protein acylation

A bioorthogonal chemical reporter for fatty acid synthase–dependent protein acylation

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