Cholesterol content in cell membrane maintains surface levels of ErbB2 and confers a therapeutic vulnerability in ErbB2-positive breast cancer

Zhang, Jinrui; Li, Qiong; Wu, Yueguang; Wang, Duchuang; Xu, Lu; Zhang, Yang; Wang, Shanshan; Wang, Taishu; Liu, Fang; Zaky, Mohamed Y.; Hou, Shuai; Liu, Shuyan; Zou, Kun; Lei, Hetian; Zou, Lijuan; Zhang, Yingqiu; Liu, Han

doi:10.1186/s12964-019-0328-4

Cited by 87 publications

(83 citation statements)

References 45 publications

(36 reference statements)

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“…For instance, the tyrosine kinase ErbB2, which is overexpressed in several breast cancers, is internalized and degraded upon knockdown of flotillin-1 or flotillin-2 [108,109]. In agreement with the idea that rafts may prevent uptake of ErbB2 from the cell surface is the finding that lowering the cellular CHOL content by addition of lovostatin, an inhibitor of CHOL synthesis, will mediate internalization of ErbB2 [110]. Because of facilitated internalization, also ErbB2-mediated signaling is reduced [108].…”

Section: Flotillinsmentioning

confidence: 55%

The role of lipid species in membranes and cancer-related changes

Skotland

Kavaliauskiene

Sandvig

2020

Cancer Metastasis Rev

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Several studies have demonstrated interactions between the two leaflets in membrane bilayers and the importance of specific lipid species for such interaction and membrane function. We here discuss these investigations with a focus on the sphingolipid and cholesterol-rich lipid membrane domains called lipid rafts, including the small flask-shaped invaginations called caveolae, and the importance of such membrane structures in cell biology and cancer. We discuss the possible interactions between the very long-chain sphingolipids in the outer leaflet of the plasma membrane and the phosphatidylserine species PS 18:0/18:1 in the inner leaflet and the importance of cholesterol for such interactions. We challenge the view that lipid rafts contain a large fraction of lipids with two saturated fatty acyl groups and argue that it is important in future studies of membrane models to use asymmetric membrane bilayers with lipid species commonly found in cellular membranes. We also discuss the need for more quantitative lipidomic studies in order to understand membrane function and structure in general, and the importance of lipid rafts in biological systems. Finally, we discuss cancer-related changes in lipid rafts and lipid composition, with a special focus on changes in glycosphingolipids and the possibility of using lipid therapy for cancer treatment.

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Section: Flotillinsmentioning

confidence: 55%

The role of lipid species in membranes and cancer-related changes

Skotland

Kavaliauskiene

Sandvig

2020

Cancer Metastasis Rev

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“…152 Indeed, cholesterol-rich lipid rafts facilitate the accumulation of receptor tyrosine kinases, such as HER2 and IGF-1, to rapidly induce oncogenic signalling including PI3K-AKT. 153 In this context, inhibiting cholesterol biosynthesis may be beneficial. Overall, in order to successfully exploit cholesterol metabolism as a therapeutic target in cancer, it may be necessary to first consider how the dependency of cancer cells on cholesterol changes with disease progression.…”

Section: Fatty Acids Support Tumorigenesis and Cancer Progressionmentioning

confidence: 99%

“…144 Conversely, blocking cholesterol synthesis with statins could be more effective at inhibiting cancer initiation and proliferation at early disease stages when these tumours are more dependent on cholesterol for sustaining growth-factorinduced signalling. 153 Pro-tumorigenic signalling molecules FAs are used for the synthesis of bioactive lipids that support cellular proliferation and survival by functioning as secondary messengers in signal transduction pathways. PtdIns are among the best-characterised signalling lipids, and are composed of two FA chains connected to an inositol ring and a glycerol backbone.…”

Section: Fatty Acids Support Tumorigenesis and Cancer Progressionmentioning

confidence: 99%

Reprogramming of fatty acid metabolism in cancer

2019

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A common feature of cancer cells is their ability to rewire their metabolism to sustain the production of ATP and macromolecules needed for cell growth, division and survival. In particular, the importance of altered fatty acid metabolism in cancer has received renewed interest as, aside their principal role as structural components of the membrane matrix, they are important secondary messengers, and can also serve as fuel sources for energy production. In this review, we will examine the mechanisms through which cancer cells rewire their fatty acid metabolism with a focus on four main areas of research. (1) The role of de novo synthesis and exogenous uptake in the cellular pool of fatty acids. (2) The mechanisms through which molecular heterogeneity and oncogenic signal transduction pathways, such as PI3K-AKT-mTOR signalling, regulate fatty acid metabolism. (3) The role of fatty acids as essential mediators of cancer progression and metastasis, through remodelling of the tumour microenvironment. (4) Therapeutic strategies and considerations for successfully targeting fatty acid metabolism in cancer. Further research focusing on the complex interplay between oncogenic signalling and dysregulated fatty acid metabolism holds great promise to uncover novel metabolic vulnerabilities and improve the efficacy of targeted therapies.

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“…First, in some cancer cells, a combination strategy limits cellsurface-receptor-mediated oncogenic activation more effectively than single therapies. For instance, in breast cancer cells positive for Erb-b2 receptor tyrosine kinase (ErbB2, also known as HER2), suppression of cholesterol biosynthesis by inhibitors such as lovastatin can trigger ErbB2 internalization and degradation 122 . In this scenario, use of ErbB2 inhibitors such as lapatinib and neratinib together with lovastatin dramatically represses tumour growth.…”

Section: Enhancement Of Cd8 T Cell Function and Inhibition Of The Regmentioning

confidence: 99%

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

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C holesterol is vital for the survival and growth of mammalian cells. More than a membrane constituent, cholesterol is a precursor to bile acids and steroid hormones, which can initiate or promote colon, breast and prostate cancers 1-3 . Cholesterol can also modulate signalling pathways involved in tumourigenesis and cancer progression by covalently modifying proteins including hedgehog and smoothened 4,5 , and by facilitating the formation of specialized membrane microdomains 6,7 . Brief overview of cholesterol metabolismEvery mammalian cell can synthesize cholesterol through the mevalonate pathway (Fig. 1a). Two acetyl-CoA molecules in the cytosol condense, thus forming acetoacetyl-CoA, which reacts with the third acetyl-CoA and yields 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA). HMG-CoA is reduced to mevalonate by HMG-CoA reductase (HMGCR), the primary rate-limiting enzyme in cholesterol biosynthesis. A series of enzymatic reactions convert mevalonate to farnesyl pyrophosphate (FPP), a precursor of sterols and all non-sterol isoprenoids. The condensation of two FPP molecules to squalene commits the process to sterol production. FPP also gives rise to geranylgeranyl pyrophosphate (GGPP), and both FPP and GGPP can prenylate and activate several oncogenic proteins such as Ras 8 . Squalene is then oxidized by squalene epoxidase (SQLE) to 2,3-epoxysqualene, which is cyclized to lanosterol. In the next steps, lanosterol follows the Bloch pathway, the Kandutsch-Russell pathway or a hybrid pathway before it is finally converted to cholesterol.Beyond de novo cholesterol biosynthesis, most cells acquire cholesterol from low-density lipoprotein (LDL) taken up from the circulation via LDL receptor (LDLR)-mediated endocytosis 9 . Enterocytes absorb dietary cholesterol from the intestinal lumen in a process involving the cholesterol transporter NPC1L1, the clathrin adaptor NUMB and the adaptor protein LIMA1 (refs. 10-12 ). Cholesterol within the cell is dynamically transported, reaching the destined membranes for structural and functional needs 13 . Cholesterol in excess of the current cellular demand is either exported from the cell by ATP-binding cassette (ABC) transporters, Reprogrammed cholesterol metabolism in cancer cellsHallmark features of cancer cholesterol metabolism. As fastproliferating cells, cancer cells require high levels of cholesterol for membrane biogenesis and other functional needs. For example, the cholesterol-derived oncometabolite 6-oxo-cholestan-3β,5α-diol, which is enriched in patients with breast cancer, binds glucocorticoid receptors and subsequently promotes tumour growth 19 . In general, cholesterol metabolism substantially contributes to cancer progression, including cell proliferation, migration and invasion 20-23 .Cholesterol metabolism produces essential membrane components as well as metabolites with a variety of biological functions. In the tumour microenvironment, cell-intrinsic and cell-extrinsic cues reprogram cholesterol metabolism and consequently promote tumourigenesis. Cholesterol-de...

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Cholesterol content in cell membrane maintains surface levels of ErbB2 and confers a therapeutic vulnerability in ErbB2-positive breast cancer

Cited by 87 publications

References 45 publications

The role of lipid species in membranes and cancer-related changes

The role of lipid species in membranes and cancer-related changes

Reprogramming of fatty acid metabolism in cancer

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

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