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.

PI(18:1/18:1) is a SCD1-derived lipokine that limits stress signaling

“…Both LC3 and p62 exhibit enhanced expression and degradation upon autophagy induction, and, thus, our observations can result from decreased or increased autophagic flux 108 . This balance might also provide a rational for seemingly contradictory findings on MUFA supplementation and SCD1 inhibition, which have been proposed to either increase or decrease the autophagic flux 109 . Interestingly, Ppp2ca forms a complex with B55α and dephosphorylates ULK1 (S637) 42 , which might explain the autophagy-regulatory activity of PI(18:1/18:1) under cytotoxic stress.…”

Tracking the Molecular Scenarios for Tumorigenic Remodeling of Extracellular Matrix Based on Gene Expression Profiling in Equine Skin Neoplasia Models

“…The SCD1 gene that encodes the enzymatic protein designated as stearoyl CoA desaturase 1 is proven to be associated with the lipid metabolism of the cell by biocatalyzing the synthesis of monosaturated fatty acids (MUFAs) from precursors that are saturated fatty acids (SFAs) [ 43 ]. This contributes to the synthesis of the basic components of biological membranes, and signaling molecules and provides a source of energy needed for the functioning of the cell [ 43 ]. Research also shows that the SCD1 gene is related to the positive regulation of autophagy.…”

“…It has been shown that its overexpression is related to the proliferation of neoplastic cells and metastasis. Furthermore, the positive regulation of the autophagy process does not occur in all types of neoplasms [ 43 ]. For example, the transcriptional repression of the SCD1 gene in human hepatocellular carcinoma (HCC) cells was brought about the activation of the apoptosis processes induced by autophagy [ 43 ], and this increased the expression of SCD1 gene in these cells, leading to a worse prognosis for patients.…”

“…Furthermore, the positive regulation of the autophagy process does not occur in all types of neoplasms [ 43 ]. For example, the transcriptional repression of the SCD1 gene in human hepatocellular carcinoma (HCC) cells was brought about the activation of the apoptosis processes induced by autophagy [ 43 ], and this increased the expression of SCD1 gene in these cells, leading to a worse prognosis for patients. The differentiation of influences on the process of autophagy is explained by the heterogeneous structure of the neoplastic tissue [ 43 ].…”

Tumor Glucose and Fatty Acid Metabolism in the Context of Anthracycline and Taxane-Based (Neo)Adjuvant Chemotherapy in Breast Carcinomas

“…It is worth mentioning the stearoyl-CoA desaturase 1 (SCD1) enzyme as another rate-limiting enzyme in fatty acid synthesis that converts saturated acids to monounsaturated fatty acids (MUFAs) involved in many biological processes (are major constituent of biological structures such as membranes and can also function as or modify signaling molecules). Accordingly more and more studies highlight different roles of SCD1 like modulation of autophagy ( 196 ) others discussing the involvements of SCD1 in regulation of cancer stem cells ( 197 ) and in the promotion of cancer cell proliferation, migration and metastasis ( 198 ). Cancer cells presenting with high degree of membrane saturation are known to be less sensitive to oxidative stress induced by agents like ACs.…”