Pro-inflammation NF-κB signaling triggers a positive feedback via enhancing cholesterol accumulation in liver cancer cells

He, Min; Zhang, Wenhui; Dong, Youhai; Wang, Lishun; Fang, Tingting; Tang, Wenyi; Lv, Bei; Chen, Guanglang; Yang, Biwei; Huang, Peixin; Xia, Jinglin

doi:10.1186/s13046-017-0490-8

Cited by 63 publications

(58 citation statements)

References 43 publications

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“…Inflammation is closely associated with cancer development through multiple mechanisms 67 . In hepatocellular carcinoma cells, treatment with the pro-inflammatory factor lipopolysaccharide activates both cholesterol biosynthesis and uptake 68 . This effect is mediated by two components of the NF-κB signalling pathway, IKKα and TAB3, which are negatively regulated by miR-195.…”

Section: Enriched Cholesterol Derivatives: Cholesteryl Esters and Oxymentioning

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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Section: Enriched Cholesterol Derivatives: Cholesteryl Esters and Oxymentioning

confidence: 99%

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

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“…CE was found to be modestly higher in HCC tissues compared to adjacent non-tumorous tissues, while FC was not changed, suggesting that their ratio is increased in the tumor (15). Cellular cholesterol synthesis is enhanced in liver cancer cells, and sterol regulatory element-binding transcription factor 2 and low-density lipoprotein receptor expression are induced (29). Higher endogenous cholesterol biosynthesis and uptake of low-density lipoprotein particles are essential for cell proliferation and survival (30).…”

Section: Discussionmentioning

confidence: 99%

Diagnostic Value of Systemic Cholesteryl Ester/Free Cholesterol Ratio in Hepatocellular Carcinoma

Krautbauer

Weiss

Wiest

et al. 2017

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“…The procedures were performed as described [13]. Preparation of nonreducing PAGE gel and protein sample was as follows: preparation of the nonreducing gel was according to the second part of the concentrated rubber and separation gel preparation scheme, without adding SDS.…”

Section: Western Blotmentioning

confidence: 99%

Protein convertase subtilisin/Kexin type 9 inhibits hepatocellular carcinoma growth by interacting with GSTP1 and suppressing the JNK signaling pathway

Fang

et al. 2020

Preprint

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Background PCSK9 has been found to be closely related to the occurrence and development of a variety of tumors. However, the concrete role of PCSK9 and its relationship with HCC development is largely unknown. Methods The expression levels of PCSK9 in HCC tissues and HCC cell lines were determined by quantitative real-time polymerase chain reaction (qRT-PCR), western blot and immunohistochemistry assays. The effects of PCSK9 expression on HCC biological traits were investigated by overexpressing and downregulating PCSK9 protein in vivo and in vitro. The mechanism by which PCSK9 mediates the depolymerization of the GSTP1 dimer and the phosphorylation of the JNK signaling pathway was further investigated. Results PCSK9 is downregulated in human HCC tissues. HCC cell proliferation, cell cycle phase distribution and apoptosis were inhibited by PCSK9 in vitro. PCSK9 suppresses tumor growth and metastasis of HCC in vivo. PCSK9 interacts with GSTP1 and promotes the depolymerization of the GSTP1 dimer and inactivation of the JNK signaling pathway. Furthermore, low PCSK9 protein expression in primary HCC tissues correlated with worse clinical outcomes. Conclusions PCSK9 inhibits HCC cell proliferation, cell cycle phase distribution and apoptosis by interacting with GSTP1 and suppressing the JNK signaling pathway, suggesting that PCSK9 might act as a tumor suppressor and may serve as a therapeutic target for the treatment of HCC.

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Pro-inflammation NF-κB signaling triggers a positive feedback via enhancing cholesterol accumulation in liver cancer cells

Cited by 63 publications

References 43 publications

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Diagnostic Value of Systemic Cholesteryl Ester/Free Cholesterol Ratio in Hepatocellular Carcinoma

Protein convertase subtilisin/Kexin type 9 inhibits hepatocellular carcinoma growth by interacting with GSTP1 and suppressing the JNK signaling pathway

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