The Stearoyl-CoA Desaturase-1 (Desat1) in Drosophila cooperated with Myc to Induce Autophagy and Growth, a Potential New Link to Tumor Survival

Abstract

Lipids are an important energy supply in our cells and can be stored or used to produce macromolecules during lipogenesis when cells experience nutrient starvation. Our proteomic analysis reveals that the Drosophila homologue of human Stearoyl-CoA desaturase-1 (Desat1) is an indirect target of Myc in fat cells. Stearoyl-CoA desaturases are key enzymes in the synthesis of monounsaturated fatty acids critical for the formation of complex lipids such as triglycerides and phospholipids. Their function is fundamental for cellular physiology, however in tumors, overexpression of SCD-1 and SCD-5 has been found frequently associated with a poor prognosis. Another gene that is often upregulated in tumors is the proto-oncogene c-myc, where its overexpression or increased protein stability, favor cellular growth. Here, we report a potential link between Myc and Desat1 to control autophagy and growth. Using Drosophila, we found that expression of Desat1, in metabolic tissues like the fat body, in the gut and in epithelial cells, is necessary for Myc function to induce autophagy a cell eating mechanism important for energy production. In addition, we observed that reduction of Desat1 affects Myc ability to induce growth in epithelial cells. Our data also identify, in prostatic tumor cells, a significant correlation between the expression of Myc and SCD-1 proteins, suggesting the existence of a potential functional relationship between the activities of these proteins in sustaining tumor progression.

Myc as a Regulator of Ribosome Biogenesis and Cell Competition: A Link to Cancer

“…Notably, in Drosophila these cellular metabolic events are highly conserved; indeed, we showed that, when overexpressed in a metabolic tissue like the fat body, Myc increases the expression of enzymes of the glycolytic flux and of lipid metabolism, resulting in increased levels of fats and glucose storage and consumption. Moreover, Myc in fat cells promoted survival pathways, like autophagy, allowing the animals to survive in low nutrient conditions [77,78]. In addition, animals expressing Myc in fat cells are bigger in size, phenocopying flies overexpressing Myc ubiquitously [33], thus suggesting a role for Myc in the control of non-autonomous pathways that regulate animal growth.…”

Autophagy as an emerging target in cardiorenal metabolic disease: From pathophysiology to management

“…Saturated and unsaturated fatty acids including palmitate and oleate stimulate autophagy, via distinct signaling mechanisms such as EIF2AK2 (or PKR) and MAPK8 (or JNK1 ) (Shen, et al, 2012). Stearoyl-CoA desaturase (SCD), which converts saturated lipids into monounsaturated lipids, promotes autophagy with a high content of unsaturated fatty acids in autophagy membranes (Paiardi, et al, 2017). SCD1 is required for early autophagosome formation and supplementation of oleate may rescue SCD1 inhibition-induced autophagic anomalies (Ogasawara, et al, 2014).…”

Drosophila melanogaster: A Model Organism to Study Cancer

“…Therefore, Myc is strictly controlled both transcriptionally and post-translationally, where its protein stability is controlled by phosphorylation events downstream of RAS/ERK and GSK3β kinases with a signaling conserved in flies and mammals (Galletti et al, 2009; Parisi et al, 2011). Myc regulation of the cellular metabolic milieu is highly similar in Drosophila to the regulation found in tumor cells (DeBerardinis et al, 2008), indeed it was shown that in cells undergoing to a metabolic stress (starvation or competitive environment), expression of Myc switched their metabolism to increase glycolysis, glutaminolysis (Parisi et al, 2013; de la Cova et al, 2014; Hsieh et al, 2015), or lipid metabolism to favor survival by inducing autophagy (Parisi et al, 2013; Paiardi et al, 2017). Fascinatingly, these evolutionary functions of Myc to control mass and metabolism, resulted in the selective advantage of growth of epithelial cells described as cell competition and characterized in the monolayer epithelia composing Drosophila's imaginal discs (Johnston, 2014).…”

“…Interestingly, we observed that Myc in Drosophila induced autophagy in the fat body and this was enough to enhance survival of the whole animals upon starvation (Parisi et al, 2013). We linked this effect with the ability of Myc to increase desat1, a Stearoyl-CoA desaturase-1 (SCD1) key enzyme in the synthesis of lipids, that we found co-expressed with Myc in human prostatic tumors (Paiardi et al, 2017).…”