Contribution of serum lipids and cholesterol cellular metabolism in lung cancer development and progression

Abstract

Neoplasms of the lungs are the leading cause of cancer incidence and mortality worldwide. Although immunotherapy has increased the overall survival of patients with lung cancer, there is the need to improve this treatment. At this regard, blood lipid levels are thought to be linked to cancer risk and thus a preventive intervention through regulation of the nutrition of patients with lung cancer is gaining much attention. In this study, we therefore asked about the contribution of serum lipids and cholesterol cellular metabolism in lung cancer development and progression. We measured different serum lipids and analyzed cholesterol synthesis enzymes 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) and acetyl-coenzyme A cholesterol acetyltransferase 1 (ACAT1) as well as the cholesterol cellular export protein ATP-binding cassette (ABC) A-1 mRNA by quantitative PCR (qPCR) in the control and tumoral regions of post-surgery lung tissues to analyze the accumulation of cholesterol in cancer cells in a cohort of patients with lung adenocarcinoma (LUAD). We found that triglycerides in serum directly correlated with the body mass index (BMI) in patients with LUAD. By contrast, we found that high-density lipoprotein (HDL) cholesterol inversely correlated with the BMI, C-reactive protein (CRP) and overall survival and total cholesterol inversely correlated with the tumor diameter, serum CRP and overall survival in these LUAD patients. Functionally, the role of cholesterol is indispensable for the growth and development of normal animal cells where it is tightly regulated. Excess of cellular cholesterol regulated by HMGCR is converted to cholesteryl esters by the enzyme ACAT1 and exported extracellularly by the cholesterol transporter ABCA1. Here we found HMGCR and ACAT1 upregulated and ABCA1 downregulated in the lung’s tumoral region of our LUAD cohort, indicating cholesterol dysregulated cellular export in lung tumor cells.

Nanometer Resolution Mass Spectro-Microtomography for In-Depth Anatomical Profiling of Single Cells

“…Interestingly, the ratio of cholesterol to phosphocholine fragments ( I 386.6 / I 184.1 ) showed a significant upregulation trend in cancer cells (Figure e), indicating a higher expression of cholesterol than in normal cells. Cholesterol, as one of the main components of cell membranes, can regulate many properties of cell membranes. , It has been reported that a high level of membrane cholesterol can decrease cell stiffness to facilitate malignant transformation and tumor progression. , Our results intuitively confirmed the high expression of cholesterol on the cancer cell membranes at the molecular level and revealed a potential target to improve the effectiveness of cancer therapies. The above results implied a bright application prospect of our current method in the omic analysis of cell membranes.…”

“…Cholesterol, as one of the main components of cell membranes, can regulate many properties of cell membranes. 54,55 It has been reported that a high level of membrane cholesterol can decrease cell stiffness to facilitate malignant transformation and tumor progression. 56,57 Our results intuitively confirmed the high expression of cholesterol on the cancer cell membranes at the molecular level and revealed a potential target to improve the effectiveness of cancer therapies.…”

Identification of Plasma Lipid Alterations Associated with Melanoma Metastasis

“…In a study by Hartmann et al, enzymes responsible for intracellular cholesterol ester accumulation (HMGCR and ACAT1) were overexpressed, and the expression of the transporter responsible for their release (ABCA1) was downregulated in lung tumors [39]. This supports our findings that reduced plasma levels of various cholesterol esters, such as CE(12:0), CE(14:0), and CE(15:0), were associated with a higher probability of metastasis and, not surprisingly, patient mortality.…”

Predictive and prognostic role of early apolipoprotein A‐I alteration in recurrent or metastatic nasopharyngeal carcinoma patients treated with anti‐PD‐1 therapy

“… 23 , 24 Otherwise, a recent study indicated that 3‐hydroxy‐3‐methyl‐glutaryl‐CoA reductase (HMGCR) and acetyl‐coenzyme A cholesterol acetyltransferase 1 (ACAT1) upregulated and ATP‐binding cassette (ABC)A1 downregulated in the lung adenocarcinoma tumor region, which would induce cholesterol dysregulated cellular export. 25 The initiation of ICI therapy may cause tumor cell necrosis, then the serum cholesterol levels would increase. Based on these findings, we hypothesized that early alteration of serum lipid levels could be associated with the efficacy of anti‐PD‐1‐based therapy in R/M NPC patients.…”