Rapamycin Regulates Stearoyl CoA Desaturase 1 Expression in Breast Cancer

278

266

Although targeting cancer metabolism is a promising therapeutic strategy, clinical success will depend on an accurate diagnostic identification of tumor subtypes with specific metabolic requirements. Through broad metabolite profiling, we successfully identified three highly distinct metabolic subtypes in pancreatic ductal adenocarcinoma (PDAC). One subtype was defined by reduced proliferative capacity, whereas the other two subtypes (glycolytic and lipogenic) showed distinct metabolite levels associated with glycolysis, lipogenesis, and redox pathways, confirmed at the transcriptional level. The glycolytic and lipogenic subtypes showed striking differences in glucose and glutamine utilization, as well as mitochondrial function, and corresponded to differences in cell sensitivity to inhibitors of glycolysis, glutamine metabolism, lipid synthesis, and redox balance. In PDAC clinical samples, the lipogenic subtype associated with the epithelial (classical) subtype, whereas the glycolytic subtype strongly associated with the mesenchymal (QM-PDA) subtype, suggesting functional relevance in disease progression. Pharmacogenomic screening of an additional ∼200 non-PDAC cell lines validated the association between mesenchymal status and metabolic drug response in other tumor indications. Our findings highlight the utility of broad metabolite profiling to predict sensitivity of tumors to a variety of metabolic inhibitors.metabolite profiling | metabolic subtypes in PDAC | glycolysis | lipid synthesis | biomarkers for metabolic inhibitors M etabolic reprogramming during tumorigenesis is an essential process in nearly all cancer cells. Tumors share a common phenotype of uncontrolled cell proliferation and must efficiently generate the energy and macromolecules required for cellular growth. The first example of metabolic reprogramming was discovered more than 80 y ago by Otto Warburg: tumor cells can shift from oxidative to fermentative metabolism in the course of oncogenesis (1). More recently, there has been a resurgence of interest in targeting cancer metabolism (2-4) because it may not only be effective in inhibiting tumor growth, but may also provide a therapeutic window (5, 6). For example, inactivation of lactate dehydrogenase-A (LDHA), an enzyme that catalyzes the final step of aerobic glycolysis, thereby reducing pyruvate to lactate, decreases tumorigenesis and induces regression of established tumors in mouse models of lung cancer driven by oncogenic KRAS or epidermal growth factor receptor (EGFR) while minimally affecting normal cell function (7). The finding that cancers have altered metabolism has prompted substantial investigation, both preclinically and in clinical trials, of several metabolically targeted agents, including those that elevate reactive oxygen species (ROS) or block glycolysis, lipid synthesis, mitochondrial function, and glutamine synthesis pathways (8).The identification of distinct metabolic reprogramming events or metabolic subtypes in cancer may inform patient selection for investigational...

Section: Discussionmentioning

confidence: 99%

Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors

Daemen¹,

Peterson²,

Sahu³

et al. 2015

278

266

“…A previous study in breast cancer cell lines showed that siRNA knockdown of eukaryotic initiation factor 4E inhibits SREBP-1 processing and that expression of a nonphosphorylatable 4E-BP1 mutant inhibits transcriptional activity of a fatty acid biosynthesis reporter gene (23). We asked if 4E-BP1 regulated the expression of SREBP2 and its target genes.…”

Section: Rapamycin-resistant Role For Mtorc1 In Regulating Cholesterolmentioning

confidence: 96%

“…SREBP proteins are synthesized as precursors that reside in the endoplasmic reticulum membrane, and, when cellular sterol levels are low, SREBP is processed in the Golgi apparatus to release the Nterminal fragment that acts as a transcription factor to control its own expression and the expression of lipid biosynthesis and uptake genes (19,20). Recent studies that used rapamycin have established a role for mTOR in regulating SREBP-1 processing and the expression of fatty acid biosynthetic genes (21)(22)(23). However, conflicting data have been obtained by groups attempting to use rapamycin to study cholesterol biosynthesis.…”

mentioning

confidence: 99%

The mammalian target of rapamycin regulates cholesterol biosynthetic gene expression and exhibits a rapamycin-resistant transcriptional profile

Wang

Ducker

Barczak

et al. 2011

The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes, so there is great interest in understanding the complete spectrum of mTOR-regulated networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin inhibits only a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. A number of studies have highlighted mTORC1 as a regulator of lipid homeostasis. We show that the ATP-competitive inhibitor PP242, but not rapamycin, significantly down-regulates cholesterol biosynthesis genes in a 4E-BP1-dependent manner in NIH 3T3 cells, whereas S6 kinase 1 is the dominant regulator in hepatocellular carcinoma cells. To identify other rapamycin-resistant transcriptional outputs of mTOR, we compared the expression profiles of NIH 3T3 cells treated with rapamycin versus PP242. PP242 caused 1,666 genes to be differentially expressed whereas rapamycin affected only 88 genes. Our analysis provides a genomewide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin.sterol regulatory element-binding protein-2 | eIF4E-binding protein-1 phosphorylation | 3-hydroxy-3-methylglutaryl-CoA reductase | thioredoxin interacting protein | expression array

“…In addition, through downstream activation of mTOR, it increases protein synthesis (4). Finally, Akt induces lipogenesis through mechanisms including enzyme phosphorylation and transcriptional activation, like mTOR-dependent activation of SREBP1 (5,6).…”

mentioning

confidence: 99%

Hypoxic and Ras-transformed cells support growth by scavenging unsaturated fatty acids from lysophospholipids

Kamphorst

Cross

Fan

et al. 2013

583

530

Cancer cell growth requires fatty acids to replicate cellular membranes. The kinase Akt is known to up-regulate fatty acid synthesis and desaturation, which is carried out by the oxygen-consuming enzyme stearoyl-CoA desaturase (SCD)1. We used 13 C tracers and lipidomics to probe fatty acid metabolism, including desaturation, as a function of oncogene expression and oxygen availability. During hypoxia, flux from glucose to acetyl-CoA decreases, and the fractional contribution of glutamine to fatty acid synthesis increases. In addition, we find that hypoxic cells bypass de novo lipogenesis, and thus, both the need for acetyl-CoA and the oxygen-dependent SCD1-reaction, by scavenging serum fatty acids. The preferred substrates for scavenging are phospholipids with one fatty acid tail (lysophospholipids). Hypoxic reprogramming of de novo lipogenesis can be reproduced in normoxic cells by Ras activation. This renders Ras-driven cells, both in culture and in allografts, resistant to SCD1 inhibition. Thus, a mechanism by which oncogenic Ras confers metabolic robustness is through lipid scavenging.isotope tracing | lipogenesis in cancer | lipid metabolism