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.

CD147 reprograms fatty acid metabolism in hepatocellular carcinoma cells through Akt/mTOR/SREBP1c and P38/PPARα pathways

“…To test this hypothesis, pcDNA3.1-SREBP1c or pSilencer™3.1-shPPARα plasmid were tansfected into HCC cells (Figures 8A and S8A) to construct stable cell lines. We found that CD147 knockout or knockdown SREBP1c has been observed in tumor tissues including liver, prostate and ovarian cancers [32]. Several studies have demonstrated that the expression and activity of SREBP1c are tightly regulated by several well-known oncoproteins.…”

Signal Transduction in Cancer

“…mTORC1 can also stimulate pyrimidine biosynthesis via S6K1 (Ben-Sahra et al 2013;Nakashima et al 2013). Akt/mTORC1 promotes lipid synthesis by activating the transcription factor sterol-response-element-binding protein 1 (SREBP), a key regulator of lipid synthesis that is required for tumorigenicity (Bakan and Laplante 2012;Jeon and Osborne 2012;Guo et al 2013). Loss of SREBP uncouples fatty acid synthase activity from stearoyl-CoAdesaturase-1-mediated desaturation.…”

Arginine Methylation of SREBP1a via PRMT5 Promotes De Novo Lipogenesis and Tumor Growth

“…SREBP is essential to maintain the balance between protein and lipid biosynthesis, and in turn, it is involved in the progression, migration, or poor prognosis of cancer (8)(9)(10). Drugs targeting SREBP1-triggered upregulation of lipogenesis have been proven as anticancer agents in glioblastoma therapy (11). Recent evidence indicates that posttranslational modifications (PTM) of SREBP1 are essential for de novo lipogenesis.…”