Overexpression of fatty acid synthase in human gliomas correlates with the WHO tumor grade and inhibition with Orlistat reduces cell viability and triggers apoptosis

Grube, Susanne; Dünisch, Pedro; Freitag, Diana; Klausnitzer, Maren; Sakr, Yasser; Walter, Jan; Kalff, Rolf; Ewald, Christian

doi:10.1007/s11060-014-1452-z

Cited by 71 publications

(81 citation statements)

References 41 publications

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“…Treatment of orlistat alone led to decreased cholesterol, saturated and unsaturated fatty acids in tumours together with reduced FASN expression, confirming the mechanism of drug action. Previous studies have also seen a reduction in FASN expression in mouse metastatic melanoma cells and in human glioblastoma cells . This could be either due to decreased expression in a translational level or increased degradation of the FASN protein.…”

Section: Discussionmentioning

confidence: 74%

The effect of FASN inhibition on the growth and metabolism of a cisplatin‐resistant ovarian carcinoma model

Papaevangelou

Almeida

Box

et al. 2018

Intl Journal of Cancer

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Overexpression of fatty acid synthase (FASN), a key regulator of the de novo synthesis of fatty acids, has been demonstrated in a variety of cancers and is associated with poor prognosis and increased multidrug resistance. Inhibition of FASN with the anti‐obesity drug orlistat has been shown to have significant anti‐tumourigenic effects in many cancers, notably breast and prostate. In our study, we investigated whether FASN inhibition using orlistat is an effective adjunctive treatment for ovarian cancers that have become platinum resistant using a cisplatin‐resistant ovarian tumour xenograft model in mice. Mice were treated with orlistat or cisplatin or a combination and metabolite analysis and histopathology were performed on the tumours ex vivo. Orlistat decreased tumour fatty acid metabolism by inhibiting FASN, cisplatin reduced fatty acid β‐oxidation, and combination treatment delayed tumour growth and induced apoptotic and necrotic cell death in cisplatin‐resistant ovarian cancer cells over and above that with either treatment alone. Combination treatment also decreased glutamine metabolism, nucleotide and glutathione biosynthesis and fatty acid β‐oxidation. Our data suggest that orlistat chemosensitised platinum‐resistant ovarian cancer to treatment with platinum and resulted in enhanced efficacy.

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Section: Discussionmentioning

confidence: 74%

The effect of FASN inhibition on the growth and metabolism of a cisplatin‐resistant ovarian carcinoma model

Papaevangelou

Almeida

Box

et al. 2018

Intl Journal of Cancer

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“…Over-expression of FASN is also associated with glioma grade. Treatment of glioblastoma cells with FASN inhibitors resulted in a significant reduction in tumor cell viability [54]. FASN has been reported to be significantly down-regulated and decrease of FASN protein level was observed following 24 hours of metformin treatment in triple negative breast cancer cells [55].…”

Section: Discussionmentioning

confidence: 99%

Metformin treatment reduces temozolomide resistance of glioblastoma cells

Yang

et al. 2016

Oncotarget

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It has been reported that metformin acts synergistically with temozolomide (TMZ) to inhibit proliferation of glioma cells including glioblastoma multiforme (GBM). However, the molecular mechanism underlying how metformin exerts its anti-cancer effects remains elusive. We used a combined experimental and bioinformatics approach to identify genes and complex regulatory/signal transduction networks that are involved in restoring TMZ sensitivity of GBM cells after metformin treatment. First, we established TMZ resistant GBM cell lines and found that the resistant cells regained TMZ sensitivity after metformin treatment. We further identified that metformin down-regulates SOX2 expression in TMZ-resistant glioma cells, reduces neurosphere formation capacity of glioblastoma cells, and inhibits GBM xenograft growth in vivo. Finally, the global gene expression profiling data reveals that multiple pathways are involved in metformin treatment related gene expression changes, including fatty acid metabolism and RNA binding and splicing pathways. Our work provided insight of the mechanisms on potential synergistic effects of TMZ and metformin in the treatment of glioblastoma, which will in turn yield potentially translational value for clinical applications.

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“…Etomoxir, a specific and irreversible inhibitor of carnitine palmitoyl transferase I (CPT1), the rate-limiting step in beta-oxidation, inhibits respiration and growth of glioma cells, and could provide a new therapeutic option for slowing tumor growth by reducing cellular catabolic activity (Lin et al, 2017). Likewise, orlistat, an inhibitor of FASN which is used in the clinical treatment of obesity, may also hold promise for use as a therapy for malignant glioma (Grube et al, 2014). …”

Section: The Contribution Of Fatty Acids To Glioma Metabolismmentioning

confidence: 99%

Metabolic Reprogramming in Glioma

Strickland

Stoll

2017

Front. Cell Dev. Biol.

266

269

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Many cancers have long been thought to primarily metabolize glucose for energy production—a phenomenon known as the Warburg Effect, after the classic studies of Otto Warburg in the early twentieth century. Yet cancer cells also utilize other substrates, such as amino acids and fatty acids, to produce raw materials for cellular maintenance and energetic currency to accomplish cellular tasks. The contribution of these substrates is increasingly appreciated in the context of glioma, the most common form of malignant brain tumor. Multiple catabolic pathways are used for energy production within glioma cells, and are linked in many ways to anabolic pathways supporting cellular function. For example: glycolysis both supports energy production and provides carbon skeletons for the synthesis of nucleic acids; meanwhile fatty acids are used both as energetic substrates and as raw materials for lipid membranes. Furthermore, bio-energetic pathways are connected to pro-oncogenic signaling within glioma cells. For example: AMPK signaling links catabolism with cell cycle progression; mTOR signaling contributes to metabolic flexibility and cancer cell survival; the electron transport chain produces ATP and reactive oxygen species (ROS) which act as signaling molecules; Hypoxia Inducible Factors (HIFs) mediate interactions with cells and vasculature within the tumor environment. Mutations in the tumor suppressor p53, and the tricarboxylic acid cycle enzymes Isocitrate Dehydrogenase 1 and 2 have been implicated in oncogenic signaling as well as establishing metabolic phenotypes in genetically-defined subsets of malignant glioma. These pathways critically contribute to tumor biology. The aim of this review is two-fold. Firstly, we present the current state of knowledge regarding the metabolic strategies employed by malignant glioma cells, including aerobic glycolysis; the pentose phosphate pathway; one-carbon metabolism; the tricarboxylic acid cycle, which is central to amino acid metabolism; oxidative phosphorylation; and fatty acid metabolism, which significantly contributes to energy production in glioma cells. Secondly, we highlight processes (including the Randle Effect, AMPK signaling, mTOR activation, etc.) which are understood to link bio-energetic pathways with oncogenic signals, thereby allowing the glioma cell to achieve a pro-malignant state.

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Overexpression of fatty acid synthase in human gliomas correlates with the WHO tumor grade and inhibition with Orlistat reduces cell viability and triggers apoptosis

Cited by 71 publications

References 41 publications

The effect of FASN inhibition on the growth and metabolism of a cisplatin‐resistant ovarian carcinoma model

The effect of FASN inhibition on the growth and metabolism of a cisplatin‐resistant ovarian carcinoma model

Metformin treatment reduces temozolomide resistance of glioblastoma cells

Metabolic Reprogramming in Glioma

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