Targeting SREBP-1-driven lipid metabolism to treat cancer

Abstract

Metabolic reprogramming is a hallmark of cancer. Oncogenic growth signaling regulates glucose, glutamine and lipid metabolism to meet the bioenergetics and biosynthetic demands of rapidly proliferating tumor cells. Emerging evidence indicates that sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor that controls lipid metabolism, is a critical link between oncogenic signaling and tumor metabolism. We recently demonstrated that SREBP-1 is required for the survival of mutant EGFR-containing glioblastoma, and that this pro-survival metabolic pathway is mediated, in part, by SREBP-1-dependent upregulation of the fatty acid synthesis and low density lipoprotein (LDL) receptor (LDLR). These results have identified EGFR/PI3K/Akt/SREBP-1 signaling pathway that promotes growth and survival in glioblastoma, and potentially other cancer types. Here, we summarize recent insights in the understanding of cancer lipid metabolism, and discuss the evidence linking SREBP-1 with PI3K/Akt signaling-controlled glycolysis and with Myc-regulated glutaminolysis to lipid metabolism. We also discuss the development of potential drugs targeting the SREBP-1- driven lipid metabolism as anti-cancer agents.

Figure 1. Model for sterols-regulated maturation of SREBPs

The precursor SREBPs locates in the ER membrane in association with SCAP, and Insig interacts with SCAP and retains the SCAP/SREBP complex in the ER membrane in the condition of high sterol levels. SCAP will dissociate from Insig and escort SREBPs translocation to the Golgi apparatus when sterol levels drop. In the Golgi, SREBPs are cleaved sequentially by the S1P and S2P proteases and then release the mature N-terminal fragment (N), which enters the nucleus to transcribe their target genes expression.

Figure 2. PI3K/Akt signaling regulates SREBP-1-mediated lipid metabolism

The scheme at the left side shows that glycolysis is promoted by PI3K/Akt signaling via promoting GLUT translocation and activating HK2 and PFK to produce pyruvate. Following, pyruvate enters into the mitochondria and generates citrate, and some portion of citrate are released into cytoplasm and hydrolysed by ACL to produce acyl-CoA, which is the precursor for lipid synthesis. In addition, glutamine incorporates into the TCA cycle through glutaminolysis regulated by the Myc oncogene, to provide an additional energy source for cell growth, and also to produce citrate as a precursor for lipid synthesis through reductive carboxylation. The scheme at right side shows that SREBP-1 plays an integral role in mediating oncogenic signaling RTK/PI3K/Akt to fatty acid synthesis and cholesterol uptake. SREBP-1 upregulates the expression of ACL, ACC and FASN to promote fatty acid synthesis, also promotes the expression of LDLR to enhance cholesterol uptake. Activation of LXR stimulates ABCA1 expression and promotes cholesterol and phospholipids efflux, also reduces LDLR levels via upregulating Idol, a ubiquitin ligase E3. GLUT, glucose transporter; HK2, hexokinase 2; PFK, phosphofructokinase; PKM2, pyruvate kinase M2; LDH, lactate dehydrogenase; PDH, pyruvate dehydrogenase; GLS, glutaminase; EGFR, epidermal growth factor receptor; RTK, receptor tyrosine kinase.

Figure 3. Lipolysis process for triacylglycerol

Triacylglycerol (TG) stored in lipid droplet is sequentially hydrolyzed by lipases ATGL, HSL and MAGL to liberate free fatty acid (FFA) and glycerol as substrates for energy production or membrane formation. ATGL, adipose triglyceride lipase; HSL, hormone-sensitive lipase; MAGL, monoacylglycerol lipase.