Malignantly transformed cells must alter their metabolic status to stay viable in a harsh microenvironment and maintain their ability to invade and spread. Anoikis, a specific detachment‐related form of apoptotic cell death, is a potential barrier to cancer cell metastasis. Several molecular/pathway alterations have been implicated in preventing anoikis in metastatic cancers. Specific alterations in the lipid metabolism machinery (such as an increase in fatty acid uptake and synthesis) and modifications in the carbohydrate and amino acid metabolism are partially identified mechanisms associated with the anoikis resistance in various types of cancers, among other survival benefits. Following a summary of the molecular basis of the anoikis pathway, its resistance mechanisms, and the fundamentals of lipid metabolism in cancer, this article aims to elucidate the impact of lipid metabolism deviations recruited by cancer cells to escape anoikis.
Background Stearoyl-coenzyme A desaturase 1 (SCD1) is required for de novo synthesis of fatty acids. Through the fatty acid acylation process, this enzyme orchestrates post-translational modifications to proteins involved in cell development and differentiation. In this study, we used biochemical methods, immunostaining, and covalent labeling to evaluate whether a small molecule modulating unsaturated fatty acids can influence the early endodermal differentiation of human-induced pluripotent stem cells (iPSCs). Methods The hiPSCs were cultured in an endoderm-inducing medium containing activin A and defined fetal bovine serum in the presence of an SCD1 inhibitor at different time points. The cell cycles and the yields of the three germ layers (endoderm, mesoderm, and ectoderm) were assessed using flow cytometry. The expression of endoderm and pluripotency markers and the expressions of Wnt signaling pathway proteins were assessed using western blotting and RT-PCR. Total protein acylation was evaluated using a click chemistry reaction. Results When SCD1 was inhibited on the first day, the population of cells with endodermal features decreased at the end of differentiation. Moreover, early SCD1 inhibition preserved the properties of hiPSCs, preventing their shift toward mesodermal or ectodermal lineage. Also, first-day-only treatment of cells with the SCD1 inhibitor decreased β-catenin gene expression and the intensity of fluorescent emission in the click chemistry assay. The cells were effectively rescued from these effects by cotreatment with oleate. Late treatment with the inhibitor in the two subsequent days of endoderm induction did not have any significant effects on endoderm-specific markers or fluorescent intensity. Reproducible results were also obtained with human embryonic stem cells. Conclusion The small molecule SCD1 inhibitor attenuates the Wnt/β-catenin signaling pathway, conferring the maintenance of hiPSCs by opposing the initiation of endoderm differentiation. The immediate requirement for SCD1 activity in the endoderm commitment of pluripotent stem cells may be of importance in disorders of endoderm-derived organs and dysregulated metabolism. The schematic representation of the study design and main results. Activin A induces endoderm features through Smad2/3/4 and increases the expression of SCD1. SCD1 can produce MUFAs and subsequently modify the Wnt molecules. MUFA acylated/activated Wnts are secreted to interact with corresponding receptors on the target cells. β-catenin accumulates in the cytoplasm and is translocated into the nucleus after the interaction of Wnt with the receptor. Then, β-catenin increases the expression of the endoderm markers Sox17 and CXCR4.
Pregnancy is accompanied by a surge in demand for fatty acids (FAs) in order to support maternal health, as well as fetal growth and development. Of particular demand is essential for long‐chain polyunsaturated FAs. FAs are primarily obtained from dietary sources and are distributed in the body. In comparison with the use of self‐reporting approaches, measuring the FA levels within different blood compartments can present a more accurate image of nutritional, and thus tissue, FA composition. Hence, the FA profile of plasma or serum is commonly used for physiological analyses. Nevertheless, plasma and serum FAs are not yet incorporated into cell membranes, and consequently may not be a suitable reflection of the FA status of body tissues. The evaluation of erythrocyte FA levels offers a superior possibility for the following reasons: the biological fluctuation of erythrocyte FA composition is low, phospholipids account for almost all the lipid content of erythrocytes, and the FA profiles of erythrocytes represent those of tissues. Here, we elaborate on whether the status of maternal erythrocyte FAs can serve as a prognostic biomarker for reproductive health and fetomaternal complications, including embryonic and fetoplacental development, gestational length, and preeclampsia. In addition, factors with the potential of altering the maternal erythrocyte FAs such as maternal diet, lifestyle habits, genetics, and body composition are discussed.
Background: Stearoyl-coenzyme A desaturase 1 (SCD1) is required for de novo synthesis of fatty acids. This enzyme can orchestrate posttranslational modification of proteins involved in the development and differentiation of cells through the fatty acid acylation process. In this study, we evaluated whether a small molecule modulating unsaturated fatty acids influences early endodermal differentiation of induced pluripotent stem cells, using biochemical methods and immunostaining.Methods: The hiPSCs were cultured in an endoderm-inducing medium containing activin A and low defined fetal bovine serum in the presence of an SCD1 inhibitor at different time points. The yield of three germ layers endoderm, mesoderm, and ectoderm, and the cell cycle analysis were assessed using flow cytometry. The expression of endoderm and pluripotency markers, as well as the expression of Wnt signaling pathway proteins, were assessed using western blotting and RT-PCR. Total protein acylation was evaluated using a click chemistry reaction.Results: The population of cells showing endoderm features was decreased at the end of differentiation when SCD1 was inhibited on the first day. Moreover, early SCD1 inhibition preserved hiPSCs properties without a shift toward mesoderm or ectoderm. Treatment of cells with SCD1 inhibitor only on the first day decreased the β-catenin gene expression and intensity of fluorescent emission in the click chemistry. These effects were effectively rescued by cotreatment with oleate. Late treatment at two subsequent days of endoderm induction induced no significant effect on endoderm-specific markers and fluorescent intensity. Reproducible results were also obtained with a human embryonic stem cell line. Conclusion: The small molecule SCD1 inhibitor attenuates the Wnt/β-catenin signaling pathway, conferring maintenance to hiPSCs by opposing the initiation of endoderm differentiation. The immediate requirement for SCD1 activity in endoderm commitment of pluripotent stem cells may be eminent in disorders of endoderm-derived organs and dysregulated metabolism.
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