Background

Autophagy is a catabolic process by which cellular components, including lipids, proteins and organelles, are degraded inside lysosomes and then recycled, contributing to cellular homeostasis [1]. Therefore, autophagy is an essential function for the quality control of cells, but it also has a crucial role in response to nutrient and oxygen deprivation. The degraded and recycled metabolites can provide energy supplies and basic nutrients for cell survival and growth [1]. Nutrient depletion leads to mobilization of free fatty acids (FFAs) from cellular lipid stores to supply energy, thus rendering lipid metabolism and autophagy functionally intertwined processes [2].

Several studies have demonstrated a dual effect of lipids on autophagy. In different tissues and/or cell types (including muscle, pancreas, liver, colon, mammary epithelial cells and neurons) autophagy is upregulated in response to increased FFAs [3,4,5,6,7] while it is downregulated in the presence of high concentrations of specific lipid species. In particular, unsaturated FFAs, such as oleic acid, showed a striking stimulatory effect on autophagy in many cells, at least up to some concentrations (500 μM) [8,9,10]. Conversely, saturated FFAs (e.g., palmitic acid) remaining in the cytosol at higher concentrations, probably because they were not efficiently incorporated in lipid droplets, suppress autophagy [10]. One of the key regulators of the fatty acid composition of cellular lipids is stearoyl-CoA desaturase 1 (SCD1), also known as fatty acyl-CoA delta-9 desaturase, an endoplasmic reticulum-resident enzyme involved in the synthesis of monounsaturated fatty acids (MUFA) from their saturated fatty acid (SFA) precursors [11].

It has also been observed that autophagy regulates lipid metabolism. Lipophagy, a type of autophagy with a complex role in cell homeostasis, contributes to both the mobilization of stored lipid content and to the translocation of lipids for lysosomal degradation, which prevents excess lipid deposits [12]. Indeed, the inhibition of ULK1 (Unc-51 Like Autophagy Activating Kinase 1), a kinase involved in the initial stages of autophagy, decreases the transcription of SCD1 in liver cells exposed to a lipotoxic environment (e.g., by administration of palmitate), inducing an increased SFA/MUFA ratio and lipotoxic cell death [13]. Lipophagy also provides the fatty acids necessary to support mitochondrial respiration, essential for the differentiation of neutrophils, thus playing a potential role in the treatment of granulocytic leukemia [14].

Given the emerging connection between lipid metabolism and autophagy, and taking into account the dominant role of SCD1 in the cellular lipidic balance, we herein discuss the connection between SCD1 and the autophagic process, along with the modality through which this crosstalk can be therapeutically exploited.

Role of autophagy in cancer

Autophagy is a highly conserved self-digesting mechanism responsible for the constitutive turnover of damaged macromolecules and organelles. This catabolic process protects organisms against various cues, including infections, cancer, neurodegeneration, aging and cardiovascular disease [15,16,17,18,19,20,21,22,23,24,25]. Autophagy is articulated in several sequential steps, including nucleation, elongation, closure, fusion and degradation (Fig. 1a). Briefly, an expanding membrane structure (phagophore) enwraps portions of the cytoplasm, incorporating unwanted material. The phagophore expands to form the autophagosome, a double-membrane compartment engulfing cytoplasmic targets (proteins, organelles or pathogens). Afterwards, the autophagosome fuses with the lysosome for cargo degradation and the consequent recycling of nutrients.

Fig. 1
figure 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

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Although autophagy is a protective mechanism, it leads to cell death when excessively induced [26]. Thus, this process is finely regulated through a number of progressive stages governed by a complex molecular machinery (Fig. 1a). The role of autophagy in cancer has spurred intense debate in recent years. Given its ability to eliminate potentially harmful cellular components, autophagy is considered a mechanism capable of suppressing the onset of cancer. Consistently, key proteins involved in the autophagic process, including Beclin1, UVRAG, Bif-1 and ATG, act as tumor suppressors by promoting apoptosis in cancer cells [18, 27,28,29,30,31]. Nevertheless, autophagy can also sustain tumor growth by providing nutrients and energy [32,33,34]. In addition, autophagy promotes the growth and survival of cancer cells exposed to stressful conditions and the maintenance of cancer cell stemness [35,36,37]. Therefore, depending on the evolutionary stages of cancer and the type of tissue, autophagy plays different, and to some extent opposite roles, that need to be fully elucidated in the attempt of develo** targeted therapeutic strategies [25].

These functions, illustrated in Fig. 1b, have induced the scientific community to further explore the impact of autophagy on oncogenesis and tumor progression. Particular emphasis has been placed on the connection between autophagy and cancer-initiating cell (CIC) maintenance/self-renewal in several types of tumors [38]. CICs are usually hidden in the hypoxic core of solid tumors, where they enter in a quiescent state and acquire immune evasive properties [39]. Hypoxia, in addition to regulating the tumor microenvironment, induces the expression of markers involved in autophagy, consequently stimulating this pathway and promoting cell survival [40]. In breast cancer, mammospheres enriched in CICs have an increased autophagy flux compared with adherent cells [41], whereas inhibition of ATG7 decreases 3D tumor spheroid structure formation, both in terms of number and size [42]. Furthermore, some transcription factors commonly associated with pluripotency (e.g., Nanog and Sox2) were tied to induction of autophagy, suggesting a reciprocal regulation between the stem cell program and this catabolic process [37]. These observations support the role of autophagy in the self-renewal of CICs, as well as their tumorigenic capability [42].

A further point is the induction of epithelial–mesenchymal transition (EMT) by the tumor microenvironment. EMT is a reversible cellular program by which tumor epithelial cells acquire mesenchymal traits, along with migratory and invasive properties. This process implies the loss of cell-cell adhesion and the lack of adherence to the extracellular matrix, the inhibition of senescence and anoikis (a programmed cell death induced by cell detachment from the extracellular matrix) and the acquisition of immunosuppressive and CIC features [43]. The tumor microenvironment, composed of inflammatory and immune cells, extracellular matrix, soluble factors and characterized by oxygen deficit, has a crucial role in this cellular transition, through the regulation of different signaling pathways. In this context, evidence indicates that the signaling cascades related to EMT are, at least in part, regulated by autophagy at different levels, favoring the survival of disseminated tumor cells [44]. For instance, the activation of the EMT-associated transcription factors Slug and Snail induces the acquisition of a CIC phenotype and activates autophagy. In turn, autophagy regulates EMT both in terms of activation and inhibition [44]. In this perspective, the dual role that autophagy plays in cancer may be rooted in the regulation of this process.

Lipids and lipid metabolism enzymes in the regulation of the autophagic machinery

The regulation of the autophagic apparatus is mediated, during key phases, by lipids or lipid metabolism enzymes [45]. Lipids are important for the recruitment of effectors to membranes. For instance, the phospholipid PI3P controls the assembly of scaffold proteins on autophagic membranes, favouring the biogenesis of the autophagosome (Fig. 1a). PI3P is mainly synthesized via phosphorylation of phosphatidylinositol (PI) at the 3′ position of the inositol ring by class III phosphoinositide 3-kinase (PI3K). PI3K is often mutated in cancer, triggers signalling cascades that alter tumor metabolism, and has been clinically validated as an important therapeutic target [46]. Small molecules targeting PI3K have been shown to inhibit autophagy [47, 48] and to contribute to cancer cell death [47].

Another important function concerns the covalent modifications to which some proteins are subjected [45]. For example, LC3 (Microtubule-associated protein 1A/1B-light chain 3) is conjugated to the lipid phosphatidylethanolamine (PE), which triggers its stable anchorage to the phagophore membrane (Fig. 1a). This modification allows the phagophore to enlarge, forming a mature autophagosome.

A further mechanism by which lipids control autophagy involves modifications of physiochemical properties of lipid bilayers, including viscosity, rigidity, and thickness [45]. These features are widely determined by the types of lipids found in the membranes. For example, phosphatidic acid (PA), through its “cone” shape, tends to promote negative curvatures of the membranes, facilitating the budding or fusion of vesicles (Fig. 1a). Phospholipase D (PLD1) is the main lipid enzyme responsible of PA production, catalysing the hydrolysis of phosphatidylcholine (PC). PLD1 is considered a positive modulator of autophagy, since its genetic removal is associated with a reduction in the size and number of autophagosomes in the livers of starved mice [49]. Moreover, elevated PLD1 activity and expression have been observed in many tumors, where its inhibition reduced cell proliferation and migration. Consistently, the targeting of both PLD1 and autophagy, synergizing in inducing tumor cell apoptosis and tumor regression, has been proposed as potential anticancer therapy [50]. Similarly, a number of other lipid enzymes have been associated with the regulation of autophagy in cancer, including Stearoyl-CoA desaturase 1, as discussed below in the next sections.

Stearoyl-CoA desaturase 1

Structure and biochemical reaction

SCD, also known as 9-fatty acyl-CoA desaturase, is an iron-containing endoplasmic reticulum-bound enzyme that catalyzes the introduction of a double bond in the cis-9 position of saturated fatty acyl-CoAs [11, 51] (Fig. 2). The mechanism of desaturation involves NADPH, the flavoprotein cytochrome b5 reductase, the electron acceptor cytochrome b5 and molecular oxygen. This reaction is aerobic, as it requires molecular oxygen; however, the latter is not incorporated into the fatty acid chain but is released in the form of water [11]. The desaturation of a fatty acid occurs through a series of redox reactions, during which two electrons flow sequentially from NADPH to the cytochrome b5 reductase (a flavoprotein, FADH2), then to the electron acceptor cytochrome b5, to SCD, and finally to O2, which is reduced to H2O. The enzymatic complex first removes a hydrogen atom at the C-9 position and then removes the second hydrogen atom from the C-10 position. The result is the introduction of a double bond at the 9,10 position into a spectrum of methylene-interrupted fatty acyl-CoA substrates [11]. The preferred substrates are palmitoyl- and stearoyl-CoA (palmitate and stearate), which are then converted into palmitoleoyl- and oleoyl-CoA (palmitoleate and oleate), respectively [11].

Fig. 2
figure 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

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The SCD protein is localized exclusively in the endoplasmic reticulum, where it is anchored to the membrane through four transmembrane domains [51] (Fig. 2). Both the amino and carboxyl-terminal domains and eight catalytically important histidine residues (hexagonal shapes), which collectively bind iron within the catalytic center of the enzyme, are oriented toward the cytosol. Therefore, the cytosolic domain provides a structural frame for the regioselectivity and stereospecificity of the desaturation reaction [51].

Two SCD isoforms have been identified in human tissues: SCD1 and SCD5 [52,53,54]. SCD1 is the main isoform, ubiquitously expressed, with a prevalence in adipose tissue, heart, brain, liver and lungs. SCD5 is poorly expressed in adult human tissues and is mostly restricted to the brain and pancreas. While little information is available on the physiological role of SCD5, the biological functions of SCD1 and its involvement in pathological processes are intensively investigated.

SCD1: biological function and involvement in cancer

SCD1 promotes the biosynthesis of MUFAs (i.e., palmitoleate and oleate) from their SFA precursors (i.e., palmitate and stearate). MUFAs represent the substrates for the synthesis of various lipids, including phospholipids (PLs), diacylglycerols (DAGs), triacylglycerols (TAGs) and cholesteryl esters (CEs), which represent basic components of biological membranes, as well as a cellular energy source and signaling molecules [55]. Therefore, the activity of SCD1 can influence cellular membrane physiology and signaling, leading to broad effects on human physiology.

SCD1 is a key factor in lipid metabolism and body weight control. High levels of SCD1 are found in the skeletal muscle of obese subjects [56] and correlate with the development of hypertriglyceridemia, atherosclerosis, and diabetes [57]. Accordingly, SCD1-deficient mice showed reduced adiposity, increased insulin sensitivity and resistance to diet-induced obesity [58, 59].

Several studies have shown that SCD1 fuels cancer cell proliferation, tumor growth and metastasis [60,61,62,63,64] (Table 1). Increased expression of SCD1 has been correlated with cancer aggressiveness and poor prognosis across a range of tumors [64,65,66,67,68]. Moreover, SCD1 promotes the maintenance/acquisition of stem-like features, including chemoresistance and self-renewal. In non-small-cell lung cancer, CICs are characterized by SCD1-mediated stabilization and nuclear translocation of YAP/TAZ, and the consequent activation of downstream factors. Conversely, pharmacological inhibition of SCD1 with the small molecule SCD1 inhibitor MF438 induces the degradation of YAP/TAZ [69], promotes the selective apoptosis of ALDH-positive cells [70], and reverts cisplatin resistance [71]. Likewise, BRAF-mutated melanoma cell lines growing under 3D conditions and enriched in CICs overexpressed SCD1, exhibited resistance to BRAF and MEK inhibitors [72].

Table 1 SCD1 and cancer. Signalling pathways regulated by SCD1 in cancer promotion and development
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Regulation of autophagy by SCD1

The connection between SCD1 and the autophagic process was originally demonstrated in Drosophila. Kohler and colleagues observed that knock-out of a Drosophila SCD homolog, Desat1, suppressed autophagy, suggesting a role for Desat1 in controlling lipid biosynthesis and/or signaling necessary for autophagic responses [73]. Subsequently, Ogasawara et al. investigated the role of SCD1 in the autophagic process in different mammalian cell lines, including mouse embryonic fibroblasts, NIH3T3 and HeLa cells. Although in SCD1 knocked-down HeLa cells a complete suppression of autophagy was not observed, probably owing to the activity of SCD isozymes (see above) or residual SCD1 activity, the administration of an SCD1 inhibitor in murine fibroblasts strongly inhibited starvation-induced autophagy, resulting in a defective translocation of ULK1 and P62/SQSTM1 to sites of autophagosome formation. Moreover, this effect was reversed by overexpression of SCD1 or supplementation with oleic acid, the catalytic product of SCD1. The activity of SCD1 in autophagy was proposed to be restricted to the early stages of autophagosome formation by i) increasing membrane fluidity and facilitating the autophagosome formation on the endoplasmic reticulum; and ii) generating membrane curvatures through the production of truncated cone-shaped fatty acids, such as oleic acid [74]. The same research group also investigated the autophagic phenotype of the yeast mutant of OLE1, an orthologue of SCD1. They observed the failed recruitment of ATG9 (Autophagy-related protein 9) on the pre-autophagosomal structure, with consequent defects in elongation of the isolation membrane and in autophagosome formation [75]. The implication of SCD1 in this cellular mechanism has also been investigated in pancreatic β-cells, in which autophagy is essential for correct architecture and functioning [76]. SCD1 inhibition affects the autophagic flux at the level of autophagosome-lysosome fusion, enhancing β-cell dysfunction and palmitate-induced apoptosis. The link between SCD1 inhibition and autophagy/apoptosis crosstalk involves changes in intracellular membrane phospholipids and the induction of ER-to-mitochondria stress signaling. In particular, the decrease in the SCD1 activity, in addition to inducing a defective autophagosome-lysosome fusion and impairing autophagy, leads to dysfunctional ER stress, mitochondrial collapse and the activation of intrinsic apoptosis [76].

Ever since, other studies have highlighted the involvement of fatty acids metabolism in the regulation of autophagy [77, 78]. For example, Santano et al. discovered that saturated fatty acids, but not unsaturated fatty acids, can activate a type of non-canonical autophagic response that uses an intact Golgi apparatus and is independent of Beclin-1, both in vitro and in vivo [77]. More recently, it has been shown that the FAA1 enzyme, an acyl-CoA synthetase, accumulates in the nucleated phagophores and induces the activation of the fatty acids necessary for their expansion, thus allowing the initiation of autophagy [78].

The controversial role of SCD1-mediated autophagy in cancer and future research perspectives

Although several studies have suggested a positive regulation of autophagy by SCD1, this modulation appears to be controversial in cancer. While a mild autophagy reduction was observed following SCD1 inhibition [74] in cervical cancer HeLa cells, an opposite trend was reported in other tumor cell lines.

In the perspective of autophagy as a pro-survival mechanism, Ono et al. found that the inhibition of SCD1 (using both the small molecule T-3764518 and SCD1-KO) in the colon cancer cell line HCT-116 accelerated the autophagic process through the activation of AMPK, thus esca** the cytotoxic effects of SCD1 inhibition [79]. The authors speculated that the excessive accumulation of saturated fatty acids, due to SCD1 inhibition, triggers an AMPK-mediated compensative resistance mechanism able to block further fatty acid synthesis while simultaneously activating autophagy. This led to the mitigation of lipotoxicity and increased cell survival. This study concluded that targeting SCD1 should be optimized by combining inhibitors of the autophagic process. This combination may overcome resistance mechanisms, thereby inducing cell death.

As mentioned above, autophagy may also act as a promoter of cell death [30, 31]. For instance, Huang et al. reported that the pharmacological inhibition of SCD1 with CAY10566 promoted apoptosis of human hepatocellular carcinoma (HCC) cells in an autophagy-dependent manner [80]. In particular, the repression of SCD1 stimulated the autophagic process, promoting an opposite effect compared to what was observed by Ono et al., i.e., the induction of cell death rather than cell survival. These authors have also correlated the increased expression of SCD1 in HCC with a shorter overall survival in patients, suggesting that the autophagy suppression, mediated by SCD1, may contribute to the development and progression of cancer. From this perspective, the inhibition of SCD1 as a clinical treatment should be considered in association with autophagy activators, at least in HCC. A similar observation was also made by Pisanu et al. [71]. In particular, inhibition of SCD1 with MF438 led to activation of the endoplasmic reticulum stress response coupled with a marked increase in autophagy, as indicated by elevated LC3-II levels. Of note, this activation of the autophagy process was associated with the selective apoptosis of CICs [71].

Different explanations may reconcile the discrepancies observed when investigating the relationships between SCD1 and autophagy in cancer. In the next section, we describe some of the regulatory mechanisms that may explain such inconsistencies.

Different function and tissue distribution of SCD1

The variation in SCD1 gene expression levels across tissues reflects different metabolic phenotypes. Although SCD1 is a ubiquitous metabolic enzyme, it plays a key role in lipogenic tissues, such as adipose tissue and liver, where it is expressed at high levels [81] (Fig. 3a). These tissues are highly predisposed to the synthesis of fatty acids, triglycerides and cholesterol. Other districts, such as skeletal muscle, represent important sites for glutaminogenic and carbohydrate metabolism and are consistently characterized by lower levels of SCD1.

Fig. 3
figure 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

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In this scenario, it is plausible that SCD1 function is tissue-dependent and that it plays a different regulation in autophagy depending upon the biological context. A conceivable hypothesis is that tissues expressing high levels of SCD1, such as the liver, are highly dependent on the enzyme. In these contexts, SCD1 inhibition makes them particularly susceptible to autophagy activation for inducing cell death (Fig. 4a). Conversely, in tissues characterized by low SCD1 levels, such as colon and cervix (Fig. 3a) [81], the inhibition of SCD1 may have a limited effect on cell viability. Here, autophagy prevalently participates in cellular homeostasis (Fig. 4a). Furthermore, by comparing normal tissues and their neoplastic counterpart, it has been observed that the expression of SCD1 increases in almost all tumor tissues, even if the largest increase was found in the liver (Fig. 3b) [82], further strengthening the previous hypothesis.

Fig. 4
figure 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

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This picture is further complicated by the fact that cancer cells can acquire heterogeneous metabolic preferences and dependencies that markedly differ from the original tissue [83]. Indeed, it is known that mutations in oncogenes and tumor suppressors can stimulate cell-autonomous metabolic reprogramming [83]. In this way, different oncogenic drivers can produce divergent metabolic phenotypes, contributing to metabolic heterogeneity among tumors arising in the same tissue. On the other hand, tumors arising in different tissues may display divergent metabolic features even if they carry the same oncogenic drivers.

Contribution of CICs and EMT

Tumor heterogeneity may account for inconsistent findings observed in cancer. In this context, the contribution of the CIC compartment deserves increased consideration. As compared to differentiated cells, CICs are characterized by an upregulation of SCD1 coupled with increased autophagic process [38, 70], suggesting that both pathways contribute to their survival by decreasing the degree of lipotoxicity (Fig. 4c). Consequently, the inhibition of SCD1 in a heterogeneous population of tumor cells may produce different effects in the two types of cells. In particular, inhibition of SCD1 in CICs makes them extremely vulnerable to lipotoxicity cell death. Conversely, more differentiated cancer cells exhibit a lower SCD1 dependency, resulting to be less affected and more resistant to abrogation of SCD1 function (Fig. 4c). This implies that the size and the plasticity of the stem cell compartment could be decisive for the effect on the entire cell population following SCD1 inhibition.

EMT may also contribute to tumor plasticity given its reversible nature. EMT is accompanied by significant changes in lipid metabolism. It has been observed that elevated levels of SCD1 promote the migration and invasion of cancer cells [84], while its inhibition with A939572 suppresses this phenomenon in lung cancer [85] (Fig. 4c). Moreover, EMT requires autophagy to sustain the viability of potentially metastatic cancer cells. For instance, a connection between EMT-like phenotype and high autophagy flux has been reported in renal cell carcinoma [44]. Therefore, the balance between the EMT process and its reverse, the mesenchymal–epithelial transition, may be influenced by the depletion of SCD1 and consequently affect the autophagic process.

Cellular lipid composition and lipotoxicity

Numerous lines of evidence indicate the ability of fatty acids, both saturated and unsaturated, to modulate autophagy [86]. Mice fed with a high-fat diet showed the formation of double-membrane autophagosomes in the liver and increased levels of LC3-II, a marker of autophagosome formation and activity of autophagic flux [10]. Autophagy is believed to be a protective mechanism against lipotoxicity, a condition in which excessive accumulation of lipids occurs in non-adipose cells, leading to cellular dysfunction and death [2, 116]. However, new SCD1 inhibitors administrable as “pro-drugs”, have recently been developed [117, 118]. Since sebocytes, unlike other cell types, are unable to activate the prodrugs into “active drugs” (irreversible steroyl-CoA inhibitors), these inhibitors may offer the opportunity to inhibit SCD1 more specifically in tumor cells, overcoming the side effects.

The targeting of autophagy also holds promise as an anticancer treatment, especially when combined with other anticancer strategies. At the clinical level, chloroquine or hydroxychloroquine (HCQ) have been proposed as autophagy-targeting agents [119]. Nevertheless, limited efficacy and toxicity are hindering their investigation, raising the need to develop more potent and specific autophagy inhibitors [120]. Toxicity, coupled with the limited poor efficacy, justifies the search for a new generation of agents targeting autophagy, which is currently in development, including Lys05, a bisamioquinoline, and DQ661, a dimeric quinacrine [121, 122]. Lys05 was found to be approximately tenfold more potent than HCQ, due to its greater accumulation within lysosomes where it deacidifies them [121]. Regarding Lys05, a remarkable antitumor efficacy was noticed in melanoma and colorectal adenocarcinoma in in vivo experiments, even as a single agent [121]. DQ661 was also shown to deacidify the lysosomes more than traditional anti-autophagy drugs, such as chloroquine and HCQ. This drug acts by inhibiting PPT1, a glycoprotein important in the catabolism of lipid-modified protein during lysosomal degradation. The rapid accumulation of palmitoylated proteins that occurs upon the inhibition of PPT1 alters mTOR signaling and lysosomal catabolism. It substantially translates into the reduction of tumor growth in melanoma, pancreatic cancer and colorectal cancer in mouse models [122]. However, clinical trials with Lys05 and DQ661 are not yet underway.

In the studies that directly addressed the relationship between SCD1 and autophagy in cancer, combined treatments with SCD1 inhibitors and autophagy regulators, both activators and inhibitors, were proposed [79, 80]. However, as we have discussed in this review, the choice of the most effective combination is not intuitive, and should be tailored on the specific biological context i.e., type of tissue, driver mutations, tumor heterogeneity, lipid vs sugar metabolism. Hence, it is essential to achieve a deeper understanding of the complex interaction between SCD1 and autophagy in order to identify the appropriate molecular background where this combined pharmacological approach may rationally be applied.

Conclusion

Increasing evidence has shown that tumor cells have an altered lipid metabolism, affecting the production of the basic components of membranes, the synthesis and degradation of lipids for energy balance as well as the availability of lipid species with signaling functions [123]. The enzyme SCD1, necessary for the conversion of endogenous and exogenous saturated fatty acids into monounsaturated fatty acids, has been found to be up-regulated in several types of cancer [64,65,66,67,68]. Many studies have reported a role for SCD1 in promoting tumor growth and metastasis, as well as in maintaining stem cell-like phenotype [60,61,62].

SCD1 is known to have an important role in regulating lipid bilayer fluidity and curvatures [124]. Furthermore, since MUFAs are incorporated at higher levels in lipid droplets as compared to SFA [125], SCD1 may be a protective factor against SFA-induced lipotoxicity. In this review, we highlight an additional role for SCD1, regarding the modulation of autophagy, both in normal and tumor cells. In Fig. 5, the main consequences of SCD1 activity and MUFA synthesis are illustrated.

Fig. 5
figure 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

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The role of autophagy in cancer remains controversial: while it usually acts as a tumor suppressor allowing cells to remove damaged cellular contents, in other cases (often in later stages of tumor development) this mechanism helps cancer cells to survive under low oxygen and nutrient conditions, acting as a tumor promoter [25, 35]. Likewise, also the role of SCD1 in the regulation of autophagy in cancer is unclear, and further studies, aimed at clarifying the contribution of tumor heterogeneity, should be conducted. It is possible to hypothesize that in CICs or cancer cells undergoing EMT, characterized both by increased autophagy and the upregulation of SCD1 [38, 43, 70], the excess lipid content is kept under control, allowing them to resist stressful conditions. Considering that CICs and cells undergoing EMT are highly resistant to conventional cytotoxic therapies [39, 126], this hypothesis may have important clinical implications, providing the basis for the study of new combined anticancer strategies, involving both inhibitors of SCD1 and autophagy modulators.