Advertisement
Tumor metabolism: cancer cells give and take lactate
Gregg L. Semenza
Vascular Program, Institute for Cell Engineering, Departments of Pediatrics, Medicine, Oncology, and Radiation Oncology, and McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Gregg L. Semenza, 733 North Broadway, Suite 671, Baltimore, Maryland 21205, USA. Fax: (443) 287-5618; E-mail: gsemenza@jhmi.edu.
Find articles by Semenza, G. in: JCI | PubMed | Google Scholar
Published November 20, 2008 - More info
J Clin Invest. 2008;118(12):3835–3837. https://doi.org/10.1172/JCI37373.
© 2008 The American Society for Clinical Investigation
Related article:
Abstract
Tumors contain oxygenated and hypoxic regions, so the tumor cell population is heterogeneous. Hypoxic tumor cells primarily use glucose for glycolytic energy production and release lactic acid, creating a lactate gradient that mirrors the oxygen gradient in the tumor. By contrast, oxygenated tumor cells have been thought to primarily use glucose for oxidative energy production. Although lactate is generally considered a waste product, we now show that it is a prominent substrate that fuels the oxidative metabolism of oxygenated tumor cells. There is therefore a symbiosis in which glycolytic and oxidative tumor cells mutually regulate their access to energy metabolites. We identified monocarboxylate transporter 1 (MCT1) as the prominent path for lactate uptake by a human cervix squamous carcinoma cell line that preferentially utilized lactate for oxidative metabolism. Inhibiting MCT1 with α-cyano-4-hydroxycinnamate (CHC) or siRNA in these cells induced a switch from lactate-fueled respiration to glycolysis. A similar switch from lactate-fueled respiration to glycolysis by oxygenated tumor cells in both a mouse model of lung carcinoma and xenotransplanted human colorectal adenocarcinoma cells was observed after administration of CHC. This retarded tumor growth, as the hypoxic/glycolytic tumor cells died from glucose starvation, and rendered the remaining cells sensitive to irradiation. As MCT1 was found to be expressed by an array of primary human tumors, we suggest that MCT1 inhibition has clinical antitumor potential.
Authors
Pierre Sonveaux, Frédérique Végran, Thies Schroeder, Melanie C. Wergin, Julien Verrax, Zahid N. Rabbani, Christophe J. De Saedeleer, Kelly M. Kennedy, Caroline Diepart, Bénédicte F. Jordan, Michael J. Kelley, Bernard Gallez, Miriam L. Wahl, Olivier Feron, Mark W. Dewhirst
The pioneering work of Peter Vaupel and his colleagues established that the partial pressure of oxygen (pO2) within human cancers is frequently much lower than that of the surrounding normal tissue and that intratumoral hypoxia is associated with an increased risk of local spread, metastasis, and patient mortality (1). Rakesh Jain’s laboratory demonstrated that in mouse tumor xenografts, the mean pO2 and pH declined as distance from the nearest blood vessel increased (2), reflecting the switch from oxidative to glycolytic metabolism that occurs in response to reduced O2 availability.
This metabolic reprogramming is orchestrated by HIF-1 through the transcriptional activation of key genes encoding metabolic enzymes, including: LDHA, encoding lactate dehydrogenase A, which converts pyruvate to lactate (3); PDK1, encoding pyruvate dehydrogenase kinase 1, which inactivates the enzyme responsible for conversion of pyruvate to acetyl-CoA, thereby shunting pyruvate away from the mitochondria (4, 5); and BNIP3, which encodes a member of the BCL2 family that triggers selective mitochondrial autophagy (6) (Figure 1). In addition, HIF-1 transactivates GLUT1 (7) — which encodes a glucose transporter that increases glucose uptake to compensate for the fact that, compared with oxidative phosphorylation, glycolysis generates approximately 19-fold less ATP per mole of glucose — and genes encoding the glycolytic enzymes that convert glucose to pyruvate (3). The extracellular acidosis associated with hypoxic tumor cells is due to both increased H+ production and increased H+ efflux through the HIF-1–mediated transactivation of: CA9, which encodes carbonic anhydrase IX (8); MCT4, which encodes monocarboxylate transporter 4 (9); and NHE1, which encodes sodium-hydrogen exchanger 1 (10).
Figure 1Intratumoral hypoxia and metabolic symbiosis. Tumors are characterized by gradients of O2 levels, based on the distance of tumor cells from a functional blood vessel. In the schematic, tumor cells surrounding the blood vessel are well oxygenated, whereas the tumor cells more distant from the vessel are poorly oxygenated and express high levels of HIF-1. HIF-1 induces the expression of proteins that increase: uptake of glucose (e.g., glucose transporter 1 [GLUT1]); conversion of glucose to pyruvate (e.g., glycolytic enzymes [Glyc. Enz.]); generation of lactate and H+ (e.g., LDHA); and efflux of these molecules out of the cell (e.g., carbonic anhydrase IX [CA9], sodium-hydrogen exchanger 1 [NHE1], MCT4). Two moles of lactate are produced for each mole of glucose consumed by the hypoxic cell. This increase in glycolytic metabolism is associated with reduced substrate delivery to the mitochondria (through the action of pyruvate dehydrogenase kinase 1 [PDK1]) and reduced mitochondrial mass (as a result of autophagy triggered by BNIP3). As described by Sonveaux et al. in their study in this issue of the JCI (11), aerobic tumor cells express proteins that allow them to take up lactate (e.g., MCT1) and use it (e.g., LDHB), in the presence of O2, as their principal substrate for mitochondrial oxidative phosphorylation. Note that hypoxic cells generate 2 mol of ATP and 2 mol of lactate per mol of glucose consumed, whereas aerobic cells generate 36 mol of ATP per 2 mol of lactate consumed. pO2, partial pressure of oxygen.
Copyright © 2024 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)