Cholesterol esterification inhibition and gemcitabine synergistically suppress pancreatic ductal adenocarcinoma proliferation

Li, Junjie; Qu, Xiaobo; Tian, Jie; Zhang, Jian-Ting; Cheng, Ji‐Xin

doi:10.1371/journal.pone.0193318

Cited by 52 publications

(62 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, although statins are well-known cholesterol-pathway inhibitors, they might target other pathways as well. For instance, statin treatment in various cancer cells leads to [126][127][128] Kras peptide vaccine, DC vaccine, anti-PD-1 + avasimibe…”

Section: Targeting Cholesterol Metabolism For Cancer Therapymentioning

confidence: 99%

“…One possible strategy is a combination of cholesterol-esterification inhibitors with traditional chemotherapy drugs. For example, the combination of avasimibe with well-known chemotherapy drugs such as gemcitabine 126 , paclitaxel 127 or doxorubicin 128 increases antitumour effects in tumour models. Another strategy is combining cholesterol-esterification inhibitors with immunotherapies, such as anti-cancer vaccines and anti-PD-1 therapy.…”

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

confidence: 99%

See 1 more Smart Citation

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

View full text Add to dashboard Cite

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...

show abstract

Section: Targeting Cholesterol Metabolism For Cancer Therapymentioning

confidence: 99%

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

confidence: 99%

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

2020

View full text Add to dashboard Cite

show abstract

“…Among other metabolites, significant accumulation of CE due to increased ACAT-1 expression was reported in multiple cancers [11-14, 35, 36]. Suppression of CE accumulation via ACAT-1 inhibition appeared to significantly impair the tumor growth as observed in pancreatic cancer, prostate cancer and in glioma tissues [12,27,29]. These reports suggest that cholesterol esterification could be considered a novel potential target for suppression of cancer proliferation and metastasis.…”

Section: Discussionmentioning

confidence: 95%

“…Excess CE may alter tumor cell signaling to promote tumor proliferation and survival [18][19][20] and depletion of CE suppresses cancer proliferation [12,27,29]. It still not clear which signaling molecules/pathways are predominantly altered by CE/ACAT-1 levels.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Assessment of acyl-CoA cholesterol acyltransferase (ACAT-1) role in ovarian cancer progression—An in vitro study

et al. 2020

View full text Add to dashboard Cite

Abnormal accumulation of acyl-CoA cholesterol acyltransferase-1 (ACAT-1) mediated cholesterol ester has been shown to contribute to cancer progression in various cancers including leukemia, glioma, breast, pancreatic and prostate cancers. However, the significance of ACAT-1 and cholesterol esters (CE) is relatively understudied in ovarian cancer. In this in vitro study, we assessed the expression and contribution of ACAT-1 in ovarian cancer progression. We observed a significant increase in the expression of ACAT-1 and CE levels in a panel of ovarian cancer cell lines (OC-314, SKOV-3 and IGROV-1) compared to primary ovarian epithelial cells (normal controls). To confirm the tumor promoting capacity of ACAT-1, we inhibited ACAT-1 expression and activity by treating our cell lines with an ACAT inhibitor, avasimibe, or by stable transfection with ACAT-1 specific short hairpin RNA (shRNA). We observed significant suppression of cell proliferation, migration and invasion in ACAT-1 knockdown ovarian cancer cell lines compared to their respective controls (cell lines transfected with scrambled shRNA). ACAT-1 inhibition enhanced apoptosis with a concurrent increase in caspases 3/7 activity and decreased mitochondrial membrane potential. Increased generation of reactive oxygen species (ROS) coupled with increased expression of p53 may be the mechanism(s) underlying pro-apoptotic action of ACAT-1 inhibition. Additionally, ACAT-1 inhibited ovarian cancer cell lines displayed enhanced chemosensitivity to cisplatin treatment. These results suggest ACAT-1 may be a potential new target for the treatment of ovarian cancer.

show abstract

Lipid metabolism in cancer progression and therapeutic strategies

Zou

Shen

et al. 2020

MedComm

156

113

View full text Add to dashboard Cite

Dysregulated lipid metabolism represents an important metabolic alteration in cancer. Fatty acids, cholesterol, and phospholipid are the three most prevalent lipids that act as energy producers, signaling molecules, and source material for the biogenesis of cell membranes. The enhanced synthesis, storage, and uptake of lipids contribute to cancer progression. The rewiring of lipid metabolism in cancer has been linked to the activation of oncogenic signaling pathways and cross talk with the tumor microenvironment. The resulting activity favors the survival and proliferation of tumor cells in the harsh conditions within the tumor. Lipid metabolism also plays a vital role in tumor immunogenicity via effects on the function of the noncancer cells within the tumor microenvironment, especially immune‐associated cells. Targeting altered lipid metabolism pathways has shown potential as a promising anticancer therapy. Here, we review recent evidence implicating the contribution of lipid metabolic reprogramming in cancer to cancer progression, and discuss the molecular mechanisms underlying lipid metabolism rewiring in cancer, and potential therapeutic strategies directed toward lipid metabolism in cancer. This review sheds new light to fully understanding of the role of lipid metabolic reprogramming in the context of cancer and provides valuable clues on therapeutic strategies targeting lipid metabolism in cancer.

show abstract

Cholesterol esterification inhibition and gemcitabine synergistically suppress pancreatic ductal adenocarcinoma proliferation

Cited by 52 publications

References 31 publications

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Assessment of acyl-CoA cholesterol acyltransferase (ACAT-1) role in ovarian cancer progression—An in vitro study

Lipid metabolism in cancer progression and therapeutic strategies

Contact Info

Product

Resources

About