Phosphoglycerate Mutase 1 Coordinates Glycolysis and Biosynthesis to Promote Tumor Growth

Hitosugi, Taro; Zhou, Lu; Elf, Shannon; Fan, Jun; Kang, Hee-Bum; Seo, Jae Ho; Shan, Changliang; Dai, Qing; Zhang, Liang; Xie, Jingui; Gu, Ting; Jin, Peng; Alečković, Maša; LeRoy, Gary; Kang, Yibin; Sudderth, Jessica; DeBerardinis, Ralph J.; Luan, Chi Hao; Chen, Georgia Z.; Müller, Susan; Shin, Dong M.; Owonikoko, Taofeek K.; Lonial, Sagar; Arellano, Martha; Khoury, H. Jean; Khuri, Fadlo R.; Lee, Benjamin H.; Ye, Keqiang; Boggon, Titus J.; Kang, Sumin; He, Chuan; Chen, Jing

doi:10.1016/j.ccr.2012.09.020

Cited by 357 publications

(379 citation statements)

References 26 publications

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“…Enolases act downstream of phosphoglycerate mutase (PGAM1) and regulate pyruvate kinase (PK) M2 isoform (PKM2), genes that are particularly active in glycolytic tumors and have recently attracted attention for their role in serine biosynthesis through regulation of 3-phosphoglycerate dehydrogenase (PHGDH) (34). ENO2 has also been proposed as a target in ENO1-deleted glioblastomas (35).…”

Section: Discussionmentioning

confidence: 99%

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

Daemen¹,

Peterson²,

Sahu³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

314

287

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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...

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Section: Discussionmentioning

confidence: 99%

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

Daemen¹,

Peterson²,

Sahu³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

314

287

View full text Add to dashboard Cite

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“…In glycolysis, 3PG is converted to 2-phosphoglycerate (2PG) by phosphoglycerate mutase 1 (PGAM1). 2PG activates PHGDH to deplete excess 3PG, thereby promoting the synthesis of serine and preventing ox-PPP inhibition [ 126 ].…”

Section: De Novo Serine Synthesismentioning

confidence: 99%

Diverting Glycolysis to Combat Oxidative Stress

Mullarky

Cantley

2015

Innovative Medicine

143

157

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Reactive oxygen species (ROS) are an intricate part of normal cellular physiology. In excess, however, ROS can damage all three major classes of macromolecules and compromise cell viability. We briefl y discuss the physiology of ROS but focus on the mechanisms cells use to preserve redox homeostasis upon oxidative stress, with particular emphasis on glycolysis. ROS inhibits multiple glycolytic enzymes, including glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase M2, and phosphofructokinase-1. Consistently, glycolytic inhibition promotes fl ux into the oxidative arm of the pentose phosphate pathway to generate NADPH. NADPH is critically important, as it provides the reducing power that fuels the protein-based antioxidant systems and recycles oxidized glutathione. The unique ability of pyruvate kinase M2 inhibition to promote serine synthesis in the context of oxidative stress is also discussed.

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“…They do that with the aid of an enzyme called Phosphoglycerate Mutase 1. In the reference [12], the authors suggest a dynamical system for their findings in a figure at the end of the paper. In the reference [13], A. K. Laird showed that solid tumors do not grow exponentially, but rather like a Gompertz function.…”

Section: About the Referencesmentioning

confidence: 99%

The Bistability Theorem in a Model of Metastatic Cancer

Larsen¹

2016

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The main theorem of the present paper is the bistability theorem for a four dimensional cancer model, in the variables M C C GF GI , , , representing primary cancer C, metastatic cancer M C , growth factor GF and growth inhibitor GI, respectively. It says that for some values of the parameters this system is bistable, in the sense that there are exactly two positive singular points of this vector field. And one is stable and the other unstable. We also find an expression for ( )

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Phosphoglycerate Mutase 1 Coordinates Glycolysis and Biosynthesis to Promote Tumor Growth

Cited by 357 publications

References 26 publications

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

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

Diverting Glycolysis to Combat Oxidative Stress

The Bistability Theorem in a Model of Metastatic Cancer

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