ATP citrate lyase (ACLY), an important enzyme involved in lipid biogenesis linked with glucose metabolism, catalyzes the conversion of citrate to oxaloacetic acid (OAA) and acetyl-CoA. The obtained acetyl-CoA is required for lipid synthesis during membrane biogenesis, as well as for histone acetylation reactions to regulate the expression of certain proteins in aberrantly proliferating cancer cells. Studies have shown a role for ACLY in tumorigenesis whereby increased levels of the enzyme leads to increased metabolic activity via activation of Akt signaling. Increasing lines of evidence suggest that enzymes involved in lipid biogenesis play a significant role in cancer cell proliferation and progression. In many cancer types such as glioblastoma, colorectal cancer, breast cancer, non-small cell lung cancer, hepatocellular carcinoma etc., the level of ACLY has been found to be quite high as compared to normal cells. Cancer cell growth related to overexpression of ACLY can be inhibited by using chemical inhibitors or by the knockdown of ACLY gene. Inhibition of ACLY leads to changes in cancer cell metabolism that promotes tumor growth and proliferation. This review summarizes the role of ACLY in cancer development and its inhibitors in cancer treatment.

Highlights Abnormality in blood cholesterol level is significantly correlated with risk of different cancers. Majority of tumor tissue from cancer patient exhibits overexpression of LDLR and ACAT for supporting rapid cancer cell proliferation. Alteration of the cholesterol metabolism in cancer cells hampers therapeutic response. Targeting cholesterol metabolism for treatment of cancer with other conventional chemotherapeutic drugs appears to be beneficial.

BackgroundPCSK9 regulates low-density lipoprotein cholesterol (LDLc) level and has been implicated in hypercholesterolemia. Aberrant plasma lipid profile is often associated with various cancers. Clinically, the relationship between altered serum lipid level and hepatocellular carcinoma (HCC) has been documented; however, the underlying cause and implications of such dyslipidemia remain unclear.MethodsThe present study includes the use of HepG2 tumor xenograft model to study the potential role of glucose (by providing 15% glucose via drinking water) in regulating PCSK9 expression and associated hypercholesterolemia. To support in vivo findings, in vitro approaches were used by incubating HCC cells in culture medium with different glucose concentrations or treating the cells with glucose uptake inhibitors. Impact of hypercholesterolemia on chemotherapy was demonstrated by exogenously providing LDLc followed by appropriate in vitro assays.ResultsWe observed that serum and hepatic PCSK9 level is decreased in mice which were provided with glucose containing water. Interestingly, serum and tumor PCSK9 level was upregulated in HepG2-tumor-bearing mice having access to water containing glucose. Additionally, elevated LDLc is detected in sera of these mice. In vitro studies indicated that PCSK9 expression was increased by high glucose availability with potential involvement of reactive oxygen species (ROS) and sterol regulatory element binding protein-1 (SREBP-1). Furthermore, it is also demonstrated that pre-treatment of cells with LDLc diminishes cytotoxicity of sorafenib in HCC cells.ConclusionTaken together, these results suggest a regulation of PCSK9 by high glucose which could contribute, at least partly, towards understanding the cause of hypercholesterolemia in HCC and its accompanied upshots in terms of altered response of HCC cells towards cancer therapy.Electronic supplementary materialThe online version of this article (10.1186/s40170-018-0187-2) contains supplementary material, which is available to authorized users.

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Obesity has a profound influence on the progression of many diseases. It induces multi-factorial effects such as dyslipidemia, insulin resistance, diabetes, arterial hypertension, and increased incidences of cancers. Multiple mechanisms link obesity with cancer initiation and progression; however, the least studied is the role of macrophages. Nutritional overload causes adipose tissue expansion in obesity and alters the balance between pro- and anti-inflammatory macrophages, which becomes a primary cause of inflammation. The chronic low-grade inflammation driven by macrophages is also an important characteristic of cancer. Adipose tissue secretes various adipokines, namely adiponectin, leptin, IL-6, TNF-α, etc., which influence macrophage behavior and tumor progression. Furthermore, other metabolic effects of obesity, such as hyperlipidemia, hyperglycemia, and hypercholesterolemia, can also regulate macrophage functionality towards tumor cells. This review summarizes events and mechanisms by which obesity influences macrophage-tumor cell interactions. The role of macrophages in anti-cancer therapies under obese conditions, as well as the effect of macrophages on T cells to regulate tumor progression, are also highlighted.

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