Phospholipid dynamics in ex vivo lung cancer and normal lung explants

Abstract

In cancer cells, metabolic pathways are reprogrammed to promote cell proliferation and growth. While the rewiring of central biosynthetic pathways is being extensively studied, the dynamics of phospholipids in cancer cells are still poorly understood. In our study, we sought to evaluate de novo biosynthesis of glycerophospholipids (GPLs) in ex vivo lung cancer explants and corresponding normal lung tissue from six patients by utilizing a stable isotopic labeling approach. Incorporation of fully 13C-labeled glucose into the backbone of phosphatidylethanolamine (PE), phosphatidylcholine (PC), and phosphatidylinositol (PI) was analyzed by liquid chromatography/mass spectrometry. Lung cancer tissue showed significantly elevated isotopic enrichment within the glycerol backbone of PE, normalized to its incorporation into PI, compared to that in normal lung tissue; however, the size of the PE pool normalized to the size of the PI pool was smaller in tumor tissue. These findings indicate enhanced PE turnover in lung cancer tissue. Elevated biosynthesis of PE in lung cancer tissue was supported by enhanced expression of the PE biosynthesis genes ETNK2 and EPT1 and decreased expression of the PC and PI biosynthesis genes CHPT1 and CDS2, respectively, in different subtypes of lung cancer in publicly available datasets. Our study demonstrates that incorporation of glucose-derived carbons into the glycerol backbone of GPLs can be monitored to study phospholipid dynamics in tumor explants and shows that PE turnover is elevated in lung cancer tissue compared to normal lung tissue.

Lipidomic landscape in cancer: Actionable insights for membrane‐based therapy and diagnoses

“…Two plasma lipids, cholesterol esters (C18:2) and SM (22:0), were shown to discern patients with SqCC patients from high‐risk individuals and, hence, could be useful in SqCC screening and early detection 116 . PE levels have been found to be significantly elevated in lung cancer tissues compared with normal lung tissues and, thus, can serve as a potential biomarker in lung cancer 117 …”

The ETNK2 gene promotes progression of papillary thyroid carcinoma through the HIPPO pathway

“…Under normal circumstances, ETNK2 is highly expressed in the liver and reproductive tissues [13]. Some studies have confirmed that increased expression of ETNK2 is closely related to liver metastasis in gastric cancer [16], lung adenocarcinoma [18], and lung squamous cell carcinoma [18]. At present, there is no literature concerning the relationship between ETNK2 and thyroid malignant tumours, so we investigated this relationship to explore new molecular markers of PTC.…”

“…Studies have shown that methylation of the ETNK2 gene promoter helps laryngeal cancer cells resist radiation [17]. ETNK2 expression is significantly upregulated in lung adenocarcinoma and squamous cell carcinoma [18]. After silencing ETNK2 in MDA-MB-231 cells, cell viability was significantly reduced [19].…”

Platelets induce free and phospholipid-esterified 12-hydroxyeicosatetraenoic acid generation in colon cancer cells by delivering 12-lipoxygenase

“…The mechanistic clarification of this issue requires carrying out a specific study. However, it is known that cancer cells rewire their metabolism to produce more PE than healthy cells, and this is associated with enhanced expression of the genes for PE biosynthesis ( 74 ).…”