Hepatocellular carcinoma-associated hypercholesterolemia: involvement of proprotein-convertase-subtilisin-kexin type-9 (PCSK9)

Abstract

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.

Influence of cholesterol on cancer progression and therapy

“…Furthermore, the accumulation of cholesterol esters due to ACAT-1 enzyme was correlated with reduced efficacy of imatinib in CLM cells (226). Earlier, our group has reported by in vitro studies that pretreatment of hepatocellular carcinoma cells with LDLc decreases sorafenib induced cell death [232] . A similar observation was reported in lung adenocarcinoma where pretreatment or co-treatment of cholesterol with oxaliplatin or carboplatin decreased the cytotoxic potential of these drugs in A549 cells [229] .…”

“… [229] 7 Hepato-cellular Carcinoma Doxorubicin, in vitro Huh-7, HepG2 cells 7-Ketocholesterol regulate P-gp through PI3K/mTOR signaling and decreases the efficacy of Doxorubicin [230] 8 Hepato-cellular carcinoma Sorafenib in vitro HepG2, HUH7 cells Pre-treatment of LDLc decreases HCC cell death from sorafenib. [232] …”

Statins: a repurposed drug to fight cancer

“…When de novo biosynthesis is the main source of intracellular cholesterol, most cells acquire cholesterol from LDL in the circulatory system via LDLR-mediated endocytosis [ 206 ]. Proprotein-convertase-subtilisin-kexin type-9 (PCSK9) overexpression promotes lysosomal degradation of LDLR [ 207 ], leading to hypercholesterolemia and ultimately, the occurrence of hepatocellular carcinoma [ 208 ]. Excess cholesterol also produces oxysterols, which are natural ligands for liver X receptors (LXRs).…”

Beyond cholesterol metabolism: The pleiotropic effects of proprotein convertase subtilisin/kexin type 9 (PCSK9). Genetics, mutations, expression, and perspective for long‐term inhibition

“…Athavale et al demonstrated that glucose could affect PCSK9 expression and subsequently LDL‐C levels in mice bearing hepatocellular carcinoma (HCC). Indeed, they showed that both serum and tumor PCSK9 levels, along with LDL‐C levels were upregulated in HepG2‐tumor‐bearing mice having access to water containing glucose .…”