Squalene epoxidase is a bona fide oncogene by amplification with clinical relevance in breast cancer

Brown, David; Caffa, Irene; Cirmena, Gabriella; Piras, Daniela; Garuti, Anna; Gallo, M.; Alberti, Saverio; Nencioni, Alessio; Ballestrero, Alberto; Zoppoli, Gabriele

doi:10.1038/srep19435

Cited by 123 publications

(118 citation statements)

References 67 publications

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“…The model building algorithm, iMAT, was used to integrate the data and derive the metabolic models from the human metabolic network, Recon 2 [17] (1B). In line with this, enzymes of cholesterol metabolism have been suggested as potential targets for different tumors [57,58]. The developed models were then used to explain the RB-specific metabolism (3A).…”

Section: Significant Differences Between Healthy and Cancer Modelsmentioning

confidence: 96%

Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma

et al. 2018

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Retinoblastoma (RB) is a childhood eye cancer. Currently, chemotherapy, local therapy, and enucleation are the main ways in which these tumors are managed. The present work is the first study that uses constraint‐based reconstruction and analysis approaches to identify and explain RB‐specific survival strategies, which are RB tumor specific. Importantly, our model‐specific secretion profile is also found in RB1‐depleted human retinal cells in vitro and suggests that novel biomarkers involved in lipid metabolism may be important. Finally, RB‐specific synthetic lethals have been predicted as lipid and nucleoside transport proteins that can aid in novel drug target development.

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Section: Significant Differences Between Healthy and Cancer Modelsmentioning

confidence: 96%

Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma

et al. 2018

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“…Several oncogenic signals, such as PI3K/AKT/mTOR, RTK/RAS and p53, have been shown to modulate cholesterol synthesis in cancer cells but due to space limitations only selected examples are discussed below (Figure 1B). Other examples can be seen in the following references (32–37). …”

Section: Cholesterol Metabolism and Its Role In Cancermentioning

confidence: 99%

The Role of Cholesterol in Cancer

2016

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The roles played by cholesterol in cancer development and the potential of therapeutically targeting cholesterol homeostasis is a controversial area in the cancer community. Several epidemiological studies report an association between cancer and serum cholesterol levels or statin use, while others suggest that there is not one. Furthermore, the Cancer Genome Atlas (TCGA) project using next-generation sequencing has profiled the mutational status and expression levels of all the genes in diverse cancers, including those involved in cholesterol metabolism, providing correlative support for a role of the cholesterol pathway in cancer development. Finally, preclinical studies tend to more consistently support a role of cholesterol in cancer with several demonstrating that cholesterol homeostasis genes can modulate development. Due to space limitations, this review provides selected examples of the epidemiological, TCGA and preclinical data, focusing on alterations in cholesterol homeostasis and its consequent effect on patient survival. In melanoma, this focused analysis, demonstrated that enhanced expression of cholesterol synthesis genes was associated with decreased patient survival. Collectively, the studies in melanoma and other cancer types, suggested a potential role of disrupted cholesterol homeostasis in cancer development but that additional studies are needed to link population based epidemiological data, the TCGA database results and preclinical mechanistic evidence to concretely resolve this controversy.

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“…In eukaryotes, the MEV pathway is the only metabolic pathway capable of generating the isoprenoids FPP and GGPP. In tumor cells, the MEV metabolism is dysregulated78 and glucose, glutamine, and acetate serve as substrates to fuel an anabolic MEV pathway5910. 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) is the rate-limiting enzyme in the biosynthesis of MVA and cholesterol.…”

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confidence: 99%

Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells

Alizadeh

Zeki²,

Mirzaei

et al. 2017

Sci Rep

118

112

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The mevalonate (MEV) cascade is responsible for cholesterol biosynthesis and the formation of the intermediate metabolites geranylgeranylpyrophosphate (GGPP) and farnesylpyrophosphate (FPP) used in the prenylation of proteins. Here we show that the MEV cascade inhibitor simvastatin induced significant cell death in a wide range of human tumor cell lines, including glioblastoma, astrocytoma, neuroblastoma, lung adenocarcinoma, and breast cancer. Simvastatin induced apoptotic cell death via the intrinsic apoptotic pathway. In all cancer cell types tested, simvastatin-induced cell death was not rescued by cholesterol, but was dependent on GGPP- and FPP-depletion. We confirmed that simvastatin caused the translocation of the small Rho GTPases RhoA, Cdc42, and Rac1/2/3 from cell membranes to the cytosol in U251 (glioblastoma), A549 (lung adenocarcinoma) and MDA-MB-231(breast cancer). Simvastatin-induced Rho-GTP loading significantly increased in U251 cells which were reversed with MEV, FPP, GGPP. In contrast, simvastatin did not change Rho-GTP loading in A549 and MDA-MB-231. Inhibition of geranylgeranyltransferase I by GGTi-298, but not farnesyltransferase by FTi-277, induced significant cell death in U251, A549, and MDA-MB-231. These results indicate that MEV cascade inhibition by simvastatin induced the intrinsic apoptosis pathway via inhibition of Rho family prenylation and depletion of GGPP, in a variety of different human cancer cell lines.

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Squalene epoxidase is a bona fide oncogene by amplification with clinical relevance in breast cancer

Cited by 123 publications

References 67 publications

Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma

Metabolite systems profiling identifies exploitable weaknesses in retinoblastoma

The Role of Cholesterol in Cancer

Mevalonate Cascade Inhibition by Simvastatin Induces the Intrinsic Apoptosis Pathway via Depletion of Isoprenoids in Tumor Cells

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