SCD1, autophagy and cancer: implications for therapy

Abstract

Background: Autophagy is an intracellular degradation system that removes unnecessary or dysfunctional components and recycles them for other cellular functions. Over the years, a mutual regulation between lipid metabolism and autophagy has been uncovered.

Methods: This is a narrative review discussing the connection between SCD1 and the autophagic process, along with the modality through which this crosstalk can be exploited for therapeutic purposes.

Results: Fatty acids, depending on the species, can have either activating or inhibitory roles on autophagy. In turn, autophagy regulates the mobilization of fat from cellular deposits, such as lipid droplets, and removes unnecessary lipids to prevent cellular lipotoxicity. This review describes the regulation of autophagy by lipid metabolism in cancer cells, focusing on the role of stearoyl-CoA desaturase 1 (SCD1), the key enzyme involved in the synthesis of monounsaturated fatty acids. SCD1 plays an important role in cancer, promoting cell proliferation and metastasis. The role of autophagy in cancer is more complex since it can act either by protecting against the onset of cancer or by promoting tumor growth. Mounting evidence indicates that autophagy and lipid metabolism are tightly interconnected.

Conclusion: Here, we discuss controversial findings of SCD1 as an autophagy inducer or inhibitor in cancer, highlighting how these activities may result in cancer promotion or inhibition depending upon the degree of cancer heterogeneity and plasticity.

Keywords: Autophagy; Lipid metabolism; cancer.

Fig. 1

Autophagy A The basic autophagy machinery. Autophagy induction is controlled by AMPK and mTOR signaling pathways. Under nutrient/energy deficiency conditions, AMPK indirectly inhibits mTOR and directly activates ULK1 protein by the phosphorylation of activation sites at Ser-555 and Ser-637. Furthermore, ULK1 is a direct target of mTOR, whose inactivation prevents the inhibitory phosphorylation on Serine 638 and 758 of ULK1, promoting its further activation. Once activated, the ULK1 kinase complex translocates to the endoplasmic reticulum, followed by the autophagic PI3K complex I. PI3K complex phosphorylates the lipid phosphatidylinositol to generate a pool of PI3P which drives omegasome formation, recruiting other autophagy effectors and producing the active form of LC3B, commonly called LC3-II. In turn, LC3-II enables the docking of specific cargos and adaptor proteins at the phagophore membrane, such as p62, able to recognize cargos destined to be degraded by autophagy. The continuous assembly of the aforementioned complexes and the delivery of distal membrane compartments allow the phagophore to expand, enclosing a portion of the cytosol, and to form the mature autophagosome. Once formed, the autophagosome fuses with a lysosome, triggering the formation of an autolysosome. After degradation of its content by the action of lysosomal hydrolases, the recycled products are released into the cytosol to be reused by the cell. B Autophagy in cancer: two sides of the same coin. Autophagy has a complex and dual role in the pathogenesis of cancer, potentially acting either as a suppressor or a promoter of tumor development. Autophagy protects from malignant transformation by safeguarding genomic stability, removing oncogenic proteins, reducing reactive oxygen species, promoting autophagic cell death and inducing the clearance of intracellular pathogens. Likewise, autophagy favours tumor initiation and progression by providing an alternative energy source in the absence of oxygen and nutrients, promoting the resistance to anoikis, causing the maintenance of Cancer Initiating Cells and supporting the survival of senescent cells, especially in distal sites

Fig. 2

Desaturation of fatty acids by stearoyl CoA desaturase (SCD). SCD1 catalyzes the introduction of a double bond between carbons 9 and 10 of a saturated long chain acyl CoA, such as stearyl CoA. In the reaction, two electrons flow through an electron transport-desaturase complex composed by cytochrome b5 reductase, cytochrome b5 and SCD1. The final acceptor of the electrons is molecular O₂, which is reduced to H₂O

Fig. 3

SCD1 expression. A Summary of the mRNA expression pattern of SCD1 across the analyzed normal tissues. Consensus Normalized eXpression (NX) levels for 55 tissue types and 6 blood cell types, created by combining the data from the three transcriptomics datasets (HPA, GTEx and FANTOM5) using the internal normalization pipeline. Colour-coding is based on tissue groups, each consisting of tissues with functional features in common [81]. B The expression range for SCD1 across tissues in available normal and tumor RNA-Seq data. Significant differences by Mann-Whitney U test are marked with red* [82]. Source: adapted from 81, 82

Fig. 4

Impact of SCD1 inhibition on autophagy in cancer. Several factors may contribute to autophagy regulation following SCD1 inhibition. A Depending on the type of tissue and the differential expression of SCD1, inhibition of SCD1 has different repercussions on autophagy. B Cellular lipid content drives cell-fate through regulation of autophagy: survival or cell death. C Differential response to SCD1 inhibition is based on the degree of cell differentiation. D SCD1 depletion integrates with other cellular pathways, including autophagy, inflammation and ferroptosis

Fig. 5

Role of SCD1 in MUFA synthesis and their contribution to lipid balance through autophagy regulation. SCD1 is an endoplasmic reticulum-bound enzyme that catalyzes the introduction of a double bond in the cis-9 position of saturated fatty acids (SFA), promoting the biosynthesis of monounsaturated fatty acids (MUFA) and a decreased SFA/MUFA ratio. The activity of SCD1 induces three main effects on lipid homeostasis of the cell, illustrated in the figure. A MUFA are more efficiently incorporated in lipid droplets compared to SFA; B MUFA are the substrates for the synthesis of various kinds of lipids, including phospholipids, diacylglycerols, triacylglycerols, and cholesteryl esters, basic components of biological membranes as well as cellular energy source and signalling molecules. C MUFA promote lipid bilayer fluidity and curvatures, facilitating the autophagosome formation on the ER and the activation of autophagy. In turn, in addition to removing damaged components, autophagy eliminates excess saturated fatty acids. These mechanisms counteract the cellular lipotoxicity and could be particularly important for the survival of cancer cells, especially Cancer Initiating Cells, which are characterized both by increased autophagy and the upregulation of SCD1