Pyruvate and Metabolic Flexibility: Illuminating a Path Toward Selective Cancer Therapies

Olson, Kristofor A.; Schell, John C.; Rutter, Jared

doi:10.1016/j.tibs.2016.01.002

Cited by 114 publications

(107 citation statements)

References 103 publications

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“…Dichloroacetate (DCA), a structural analogue of pyruvate, represents the most-studied agent capable of inhibiting PDK activity (86). DCA-mediated PDK inhibition allows entry of pyruvate into the TCA cycle, restoration of oxidative phosphorylation in cancer cells, and diminishes metastasis (87)(88)(89).…”

Section: Distinct Metastatic Microenvironments Select For Specific Momentioning

confidence: 99%

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

et al. 2016

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Cancer cells must adapt their metabolism to meet the energetic and biosynthetic demands that accompany rapid growth of the primary tumor and colonization of distinct metastatic sites. Different stages of the metastatic cascade can also present distinct metabolic challenges to disseminating cancer cells. However, little is known regarding how changes in cellular metabolism, both within the cancer cell and the metastatic microenvironment, alter the ability of tumor cells to colonize and grow in distinct secondary sites. This review examines the concept of metabolic heterogeneity within the primary tumor, and how cancer cells are metabolically coupled with other cancer cells that comprise the tumor and cells within the tumor stroma. We examine how metabolic strategies, which are engaged by cancer cells in the primary site, change during the metastatic process. Finally, we discuss the metabolic adaptations that occur as cancer cells colonize foreign metastatic microenvironments and how cancer cells influence the metabolism of stromal cells at sites of metastasis. Through a discussion of these topics, it is clear that plasticity in tumor metabolic programs, which allows cancer cells to adapt and grow in hostile microenvironments, is emerging as an important variable that may change clinical approaches to managing metastatic disease. Cancer Res; 76(18); 5201-8. Ó2016 AACR.

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Section: Distinct Metastatic Microenvironments Select For Specific Momentioning

confidence: 99%

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

et al. 2016

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“…For broad coverage of pyruvate metabolism and historical overviews of scientific advances on understanding of MPC function beyond the intended scope of this work, the reader is referred to several review articles [21-26]. …”

Section: The Mitochondrial Pyruvate Carriermentioning

confidence: 99%

Mitochondrial pyruvate carrier function and cancer metabolism

Rauckhorst

Taylor

2016

Current Opinion in Genetics & Development

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Metabolic reprograming in cancer supports the increased biosynthesis required for unchecked proliferation. Increased glucose utilization is a defining feature of many cancers that is accompanied by altered pyruvate partitioning and mitochondrial metabolism. Cancer cells also require mitochondrial tricarboxylic acid cycle activity and electron transport chain function for biosynthetic competency and proliferation. Recent evidence demonstrates that mitochondrial pyruvate carrier (MPC) function is abnormal in some cancers and that increasing MPC activity may decrease cancer proliferation. Here we examine recent findings on MPC function and cancer metabolism. Special emphasis is placed on the compartmentalization of pyruvate metabolism and the alternative routes of metabolism that maintain the cellular biosynthetic pools required for unrestrained proliferation in cancer.

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“…As will be discussed in more detail in the sections that follow, overexpression, knockdown, and conditional alleles have been utilized to understand the role of the MPC in diverse systems including cancer and mouse models of diabetes [18, 20, 21, 38–43]. Nonetheless, reports on selective deletion in adult tissues are currently limited to pancreatic β-cells [44] and the liver [18, 20], which will be highlighted as examples of the role of the MPC in energy sensing and regulation of mitochondrial substrate selection.…”

Section: The Mitochondrial Pyruvate Carriermentioning

confidence: 99%

“…In contrast, loss of MPC activity and impaired carbohydrate oxidation may contribute to cellular transformation in cancer, where the MPC functions as a repressor of the Warburg Effect [21, 38–43]. Loss of MPC activity is associated with cancer cell stemness, and genetically increasing MPC activity decreases growth of HCT15 and HT29 colon cancer cells in spheroids and xenografts, but not in adherent culture as a monolayer [21].…”

Section: The Mitochondrial Pyruvate Carriermentioning

confidence: 99%

“…B) MPC activity promotes pyruvate entry into the TCA cycle and oxidative phosphorylation. Decreased MPC activity promotes the Warburg Effect, where glycolysis and lactate production are favored over oxidative phosphorylation [21, 38–43]. Inhibition of MCTs impairs cellular lactate export, increases MPC activity, and promotes pyruvate oxidation [38].…”

Section: Figurementioning

confidence: 99%

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Functional Properties of the Mitochondrial Carrier System

Taylor

2017

Trends in Cell Biology

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The mitochondrial carrier system (MCS) transports small molecules between mitochondria and the cytoplasm. It is integral to the core mitochondrial function to regulate cellular chemistry by metabolism. The mammalian MCS comprises the transporters of the 53 member canonical SLC25A family and a lesser number of identified non-canonical transporters. The recent discovery and investigations of the mitochondrial pyruvate carrier (MPC) illustrate the diverse effects a single mitochondrial carrier may exert on cellular function. However, the transport selectivities of many carriers remain unknown, and most have not been functionally investigated in mammalian cells. The mechanisms coordinating their function as a unified system remain undefined. Increased accessibility to molecular-genetic and metabolomic technologies now greatly enables investigation of the MCS. Continued investigation of the MCS may reveal how mitochondria encode complex regulatory information within chemical thermodynamic gradients. This understanding may enable precision modulation of cellular chemistry to counteract the dysmetabolism inherent in disease.

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Pyruvate and Metabolic Flexibility: Illuminating a Path Toward Selective Cancer Therapies

Cited by 114 publications

References 103 publications

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

Mitochondrial pyruvate carrier function and cancer metabolism

Functional Properties of the Mitochondrial Carrier System

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