Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids
ReviewStearoyl CoA desaturase-1: New insights into a central regulator of cancer metabolism
Introduction
Under standard dietary conditions, non-transformed mammalian cells convert the surplus of glucose into SFA and MUFA, which are then used for the synthesis and remodeling of phospholipids, as well as for the formation of energy-storing lipids triacylglycerols and cholesterolesters [1]. Non-transformed cells also actively incorporate and metabolize SFA and MUFA from dietary sources that will serve as substrates for lipid biosynthetic and oxidation reactions [2]. The oncogenic transformation of normal cells into neoplastic cells involves a profound reprogramming of macromolecule metabolism [3]. The constitutive changes in glucose and lipid metabolic pathways that occur during the transformation process, including critical reactions of fatty acid metabolism, are among the most common alterations found in cancer cells and tissues [4]. In pioneering work done almost a century ago, Otto Warburg's lab described the presence of highly active aerobic glycolysis as a biochemical hallmark of malignancy [5]. In 1950s, studies in tumor metabolism revealed that lipid biosynthesis, particularly the production of fatty acids, was elevated in tumors [6], [7], suggesting that cancer cells need to reconfigure the integrated network of glucose- and lipid-mediated metabolic reactions to induce and sustain the growth, multiplication and survival of cancer cells. Subsequent investigations over the years have decisively shown that lipogenic activity is an integral component of the mechanisms of carcinogenesis. Also, it raised the question of how lipid synthesis, particularly the synthesis and Δ9-desaturation of fatty acids, mechanistically contributes to the onset and progression of cancer. The production of structural, signaling and energy-yielding lipids demands not only abundant provision of fatty acid substrates for lipid metabolic reactions but, in addition, these fatty acids must possess a chemical quality that is appropriate for maintaining the functions of dividing cells [8]. For reasons still not fully understood, despite having the ability to incorporate fatty acids from the surrounding media, cancer cells have developed a highly active fatty acid biosynthetic machinery that coordinates the activation of a sequence of fatty acid biosynthetic enzymes: ATP-citrate lyase (ACLY), acetyl CoA carboxylase (ACC), fatty acid synthase (FASN), and SCD. As a result, cancer cells manufacture large amounts of SFA and MUFA that enrich every acyl-containing lipid fraction in the cell, a metabolic trait that is required for the full expression of the neoplastic phenotype in these cells. The essential role of ACLY, ACC, FAS and other fatty acid biosynthetic enzymes in the control of mammalian cell metabolism, as well as their crucial participation in oncogenic mechanisms has been extensively described in several excellent reviews [1], [4], [9], [10]. In the following sections, the present review will discuss several lines of experimental, clinical and epidemiological evidence that highlights the relevance of SCD1 as a key factor in the reprogramming of metabolic and signal transduction events that leads to cancer development.
Section snippets
Isoforms, catalytic activity and tissue distribution
The synthesis of MUFA, driven by SCD-like desaturases and other enzymes with similar functions, is an evolutionarily conserved activity that is essential for the survival of many different organismal species, from bacteria to mammalian cells [11], [12], [13], [14], [15], [16], [17], [18], [19]. SCD are Δ9-fatty acyl CoA desaturases that catalyze the formation of a double bond in the cis-delta-9 position of saturated fatty acyl CoAs, mainly palmitoyl CoA and stearoyl CoA, to produce palmitoleoyl
MUFA metabolism in cancer: clinical and epidemiological studies
Accumulating clinical and epidemiological data indicate the presence of unbalanced levels of SFA and MUFA in blood and tissues of cancer patients, which may point to an aberrant SCD1 activity in this disease. Studies in breast cancer patients showed a positive correlation of low stearic acid content with high oleic acid levels in sera with cancer emergence [61], [62]. A reduced stearic-to-oleic ratio was detected in erythrocytes of patients with various solid tumors, including pancreatic,
SCD1 and the regulation of cell proliferation
As mentioned above, the change in SFA:MUFA balance propelled by high SCD1 is not only a conspicuous marker of neoplastic transformation but also a key contributing factor to the predominantly lipogenic metabolism in cancer cells. More importantly, these biochemical changes appear to be a prerequisite for the onset of typical traits of malignant behavior, such as a high rate of cell proliferation, survival, and invasiveness, which leads to tumor formation and metastasis (Fig. 3). The crucial
SCD1 modulates critical proliferation and survival signaling pathways in cancer cells
As part of the process of oncogenic transformation, growth and survival signaling pathways were generally thought to exert a unidirectional regulatory influence on macromolecule metabolism. More recent investigations have challenged this view, suggesting that oncogenic signals and metabolic pathways, including the biosynthesis of MUFA, are subjected to a fluid cross talk that determines a synchronous regulation of the overall rate of metabolic and signaling activity. This section examines data
SCD and cancer: potential therapeutic opportunities and future directions
The well-documented anticancer effects of SCD1 inhibition have opened a new window of opportunity for the development of SCD blockers as an alternative treatment for various forms of cancer, particularly chemo-resistant types of malignancies, such as aggressive variants of lung and breast cancer. Several reviews have extensively described the increasing number of specific small molecule inhibitors of SCD1 activity that have been developed for potential therapeutic purposes [230], [231]. The
Conflict of interest
The author declares that there are no conflict of interests.
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Acknowledgements
The author is indebted to Dr. Joseph L. Dixon, Rutgers University, for his critical comments and editorial advice. The author would like to apologize to those researchers whose work in the field could not be cited in the present review due to space constrains.
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2022, Comparative Biochemistry and Physiology Part - C: Toxicology and PharmacologyCitation Excerpt :In addition to extending the carbon chain, double bonds occur within the existing carbon chain, known as unsaturation. Stearoyl-CoA (Δ9) desaturase (SCD), which can transform a UFA into a monosaturated fatty acid (MUFA), has been conserved in various animal species (Igal, 2016), but PUFAs cannot be synthesized by SCD and are instead synthesized by Δ12-desaturase and Δ15-desaturase. However, those desaturases are found only in plants and algae and do not occur in animals (Meesapyodsuk and Qiu, 2012).