An Essential Requirement for the SCAP/SREBP Signaling Axis to Protect Cancer Cells from Lipotoxicity

• Published in: Cancer research (Chicago, Ill.) Vol. 73; no. 9; pp. 2850 - 2862
• Main Authors: Williams, Kevin J., Argus, Joseph P., Zhu, Yue, Wilks, Moses Q., Marbois, Beth N., York, Autumn G., Kidani, Yoko, Pourzia, Alexandra L., Akhavan, David, Lisiero, Dominique N., Komisopoulou, Evangelia, Henkin, Amy H., Soto, Horacio, Chamberlain, Brian T., Vergnes, Laurent, Jung, Michael E., Torres, Jorge Z., Liau, Linda M., Christofk, Heather R., Prins, Robert M., Mischel, Paul S., Reue, Karen, Graeber, Thomas G., Bensinger, Steven J.
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.05.2013
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Fatty Acid Synthases - metabolism; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Medical sciences; Membrane Proteins - metabolism; Mice; Mice, Inbred NOD; Models, Statistical; Neoplasm Transplantation; Neoplasms - metabolism; Pharmacology. Drug treatments; Signal Transduction; Stearoyl-CoA Desaturase - metabolism; Sterols - metabolism; Tumors; Prevention; Signal transduction; Essential; Tumor cell
• ISSN: 0008-5472; 1538-7445; 1538-7445
• DOI: 10.1158/0008-5472.CAN-13-0382-T

The sterol regulatory element-binding proteins (SREBP) are key transcriptional regulators of lipid metabolism and cellular growth. It has been proposed that SREBP signaling regulates cellular growth through its ability to drive lipid biosynthesis. Unexpectedly, we find that loss of SREBP activity inhibits cancer cell growth and viability by uncoupling fatty acid synthesis from desaturation. Integrated lipid profiling and metabolic flux analysis revealed that cancer cells with attenuated SREBP activity maintain long-chain saturated fatty acid synthesis, while losing fatty acid desaturation capacity. We traced this defect to the uncoupling of fatty acid synthase activity from stearoyl-CoA desaturase 1 (SCD1)–mediated desaturation. This deficiency in desaturation drives an imbalance between the saturated and monounsaturated fatty acid pools resulting in severe lipotoxicity. Importantly, replenishing the monounsaturated fatty acid pool restored growth to SREBP-inhibited cells. These studies highlight the importance of fatty acid desaturation in cancer growth and provide a novel mechanistic explanation for the role of SREBPs in cancer metabolism. Cancer Res; 73(9); 2850–62. ©2013 AACR.