Synergy of Dendritic Cell Vaccines and Avasimibe in Treatment of Head and Neck Cancer in Mice

Chen, Xin; Song, Qibin; Xia, Leiming; Xu, Ximing

doi:10.12659/msm.905814

Cited by 11 publications

(12 citation statements)

References 39 publications

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“…In addition, avasimibe treatment effectively reduced regulatory T cell populations and enhanced the level of tumor‐infiltrating CD8+ T cell in a lung tumor model, while a combination of avasimibe with a Kras peptide vaccine further increased T cell immunity and improved inhibition of lung tumorigenesis 251 . CSCs‐DC vaccine combined with avasimibe was shown to have an enhanced therapeutic effect for head and neck cancer in a xenograft model 252 . In addition, treatment with an ACAT1 inhibitor can improve the antitumor efficacy of anti‐PD1 antibody therapy.…”

Section: Therapeutic Strategies Targeting Lipid Metabolism Reprogrammmentioning

confidence: 99%

Lipid metabolism in cancer progression and therapeutic strategies

Zou

Shen

et al. 2020

MedComm

157

113

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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.

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Section: Therapeutic Strategies Targeting Lipid Metabolism Reprogrammmentioning

confidence: 99%

Lipid metabolism in cancer progression and therapeutic strategies

Zou

Shen

et al. 2020

MedComm

157

113

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“…Lung, head and neck cancer, melanoma models 87,115,129 HER2, receptor tyrosine-protein kinase ErbB-2; CRC, colorectal cancer.…”

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

confidence: 99%

“…Although avasimibe treatment effectively inhibits regulatory T cell populations and increases CD8 T cell infiltration in a lung tumour model, a combination of avasimibe with a Kras peptide vaccine has stronger tumour inhibitory effects 115 . Avasimibe can also be combined with a DC vaccine to boost adaptive anti-tumour immunity, as shown in a head and neck cancer model 129 . Finally, a combination of avasimibe with anti-PD-1 therapy effectively controls melanoma growth 87 .…”

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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“…Recent studies (36–38) have also identified an association between ACAT-1 and the immune system, as inhibiting ACAT-1 expression may enhance the anti-tumor activity of cluster of differentiation (CD)8 + T cells. During T cell activation, lipid metabolism is required for membrane biosynthesis and cell growth.…”

Section: Discussionmentioning

confidence: 99%

Effect of inhibiting ACAT‑1 expression on the growth and metastasis of Lewis lung carcinoma

Qiao

Zhang

et al. 2019

Oncol Lett

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Accumulating evidence suggests that acetyl-CoA acetryltransferase 1 (ACAT-1) may mediate tumor development and metastasis. However, the specific function served by ACAT-1 in lung cancer is not well understood. Therefore, the present study initially verified that ACAT-1 was overexpressed in Lewis lung carcinoma (LLC) tissues compared with non-LLC mice and that this overexpression promoted the proliferation, invasion and metastasis of these LLC samples. Western blotting, immunofluorescence microscopy and flow cytometry allowed the present study to determine that the ACAT-1 inhibitor avasimibe significantly reduced the expression of ACAT-1 in LLC compared with LLC cells that are not treated with avasimibe (P<0.05). A combination of Cell Counting Kit-8 and wound healing assays demonstrated that downregulating ACAT-1 expression sufficiently inhibited the proliferation of LLC cells. Avasimibe promoted LLC cell apoptosis as assessed by a Annexin V/propidium iodide double staining assay. Furthermore, avasimibe inhibited tumor growth in vivo and improved immune responses, with tissue biopsies from LLC model mice exhibiting higher levels of ACAT-1 compared with in healthy controls. Altogether, the results of the present study reveal that avasimibe may inhibit the progression of LLC by downregulating the expression of ACAT-1, which may thus be a potential novel therapeutic target for lung cancer treatment.

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Synergy of Dendritic Cell Vaccines and Avasimibe in Treatment of Head and Neck Cancer in Mice

Cited by 11 publications

References 39 publications

Lipid metabolism in cancer progression and therapeutic strategies

Lipid metabolism in cancer progression and therapeutic strategies

Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities

Effect of inhibiting ACAT‑1 expression on the growth and metastasis of Lewis lung carcinoma

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