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Published OnlineFirst July 20, 2010; DOI: 10.1158/0008-5472.CAN-09-4615

Fructose Induces Transketolase Flux to Promote Pancreatic Cancer Growth Haibo Liu, Danshan Huang, David L. McArthur, et al. Cancer Res 2010;70:6368-6376. Published OnlineFirst July 20, 2010.

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Downloaded from on April 22, 2013. © 2010 American Association for Cancer Research.

Published OnlineFirst July 20, 2010; DOI: 10.1158/0008-5472.CAN-09-4615

Tumor and Stem Cell Biology

Cancer Research

Fructose Induces Transketolase Flux to Promote Pancreatic Cancer Growth Haibo Liu1, Danshan Huang1, David L. McArthur2, Laszlo G. Boros3, Nicholas Nissen4, and Anthony P. Heaney1,2

Carbohydrate metabolism via glycolysis and the tricarboxylic acid cycle is pivotal for cancer growth, and increased refined carbohydrate consumption adversely affects cancer survival. Traditionally, glucose and fructose have been considered as interchangeable monosaccharide substrates that are similarly metabolized, and little attention has been given to sugars other than glucose. However, fructose intake has increased dramatically in recent decades and cellular uptake of glucose and fructose uses distinct transporters. Here, we report that fructose provides an alternative substrate to induce pancreatic cancer cell proliferation. Importantly, fructose and glucose metabolism are quite different; in comparison with glucose, fructose induces thiaminedependent transketolase flux and is preferentially metabolized via the nonoxidative pentose phosphate pathway to synthesize nucleic acids and increase uric acid production. These findings show that cancer cells can readily metabolize fructose to increase proliferation. They have major significance for cancer patients given dietary refined fructose consumption, and indicate that efforts to reduce refined fructose intake or inhibit fructose-mediated actions may disrupt cancer growth. Cancer Res; 70(15); 6368–76. ©2010 AACR.

Cell immortalization and malignant transformation are predominantly determined by altered or aberrant gene expression that in turn modifies cellular metabolic pathways to support tumor growth, viability, and spread. Consequently, cancer cells typically have abnormal metabolism and consume glucose avidly to produce high quantities of lactic acid even in the presence of adequate oxygen, a process first noted by Warburg and colleagues (1). The nonoxidative pentose phosphate pathway (PPP), which allows six-carbon glucose conversion to five-carbon ribose for DNA or RNA synthesis, is of utmost importance for the proliferation process and produces >85% of the ribose recovered from tumor nucleic acids (2). The nonoxidative PPP, controlled by transketolase (TK) enzyme reactions, is encoded by three human TK genes: TKT, TKTL1, and TKTL2 (3, 4). Clinically, patients with extensive cancer burden have a tendency to develop thiamine depletion, which is a cofactor for TK-mediated

Authors' Affiliations: Departments of 1Medicine and 2Neurosurgery, David Geffen School of Medicine, University of California; 3 SiDMAP LLC; 4Cedars-Sinai Medical Center, Los Angeles, California Note: A.P. Heaney conceived and supervised the project and designed the experiments. H. Liu and D. Huang performed the experiments. L.G. Boros designed and performed the metabolomic experiments. D.L. McArthur carried out the biostatistical analysis. N. Nissen provided the surgically resected pancreatic cancer tissues. All authors contributed to the preparation of the manuscript. Corresponding Author: Anthony P. Heaney, David Geffen School of Medicine, University of California, Los Angeles, CA 90024. Phone: 310267-4980; Fax: 310-267-1899; E-mail: [email protected] doi: 10.1158/0008-5472.CAN-09-4615 ©2010 American Association for Cancer Research.

reactions, emphasizing the importance of the nonoxidative PPP for tumor growth. Increased obesity due to increased total energy consumption and reduced activity now contributes to 15% of U.S. cancer deaths (5, 6). In addition to higher fat intake, a large increase in refined carbohydrate intake has occurred, which itself has been hypothesized to be a risk factor for several cancers (7, 8). Eighty percent of this carbohydrate derives from added sweeteners, in which the disaccharide sucrose (50% glucose and 50% fructose) and high-fructose corn syrup (45% glucose and 55% fructose) are the main sugars (9, 10). Increased refined fructose consumption, in particular, has been highlighted as conferring greater pancreatic cancer risk than other sugars in several recent large epidemiologic studies (11, 12). Normal physiologic glucose concentration, a key substrate for cancer metabolism through glycolysis in the cytosol and through the tricarboxylic acid (TCA) cycle in mitochondria, is tightly controlled between 5 and 7 mmol/L by several hormones, including insulin and glucagon, but little is known about human circulating serum fructose levels (13). We recently observed that mean circulating fasting fructose levels were 2.5 times higher in pancreatic cancer patients in comparison with fasting serum fructose levels in healthy subjects who were in the 0.5 to 1.0 mmol/L range (14). The role, if any, of fructose as a substrate in cancer is poorly understood. The present study shows that pancreatic cancer cells grow in a range of fructose concentrations that are attainable with the current Western diet and at equivalent rates to glucose. Of major importance, we show that pancreatic cancer metabolism of fructose and glucose is very different, as fructose is a potent inducer of TKT and is preferentially used in the nonoxidative PPP to generate increased nucleic acids in comparison with glucose.


Cancer Res; 70(15) August 1, 2010

Downloaded from on April 22, 2013. © 2010 American Association for Cancer Research.

Published OnlineFirst July 20, 2010; DOI: 10.1158/0008-5472.CAN-09-4615 Fructose Induces Pancreatic Cancer Growth

Materials and Methods
Cells Human pancreatic cancer (CaPan-I, CaPan-II, HPAF2, Aspc1, Panc-1, and MiaPaCa-2) and hepatoblastoma (HepG2) cell lines were purchased in 2009 and 2010 from the American Type Culture Collection (ATCC) and used in the described experiments within 6 months after purchase. Authentication testing was performed by ATCC and includes (a) certification that each cell line is negative for Mycoplasma, bacteria, and fungi contamination; (b) confirmation of species identity and detection of possible cellular contamination or misidentification using Cytochrome c Oxidase subunit I (COI) for interspecies identification and short tandem repeat (STR) analysis (DNA profiling) for intraspecies identification; and (c) conducting of additional test methods, such as cytogenetic analysis (G-banding and fluorescence in situ hybridization), flow cytometry, and immunocytochemistry as well as consistent refinement of cell growth conditions as well as documentation systems, ensuring traceability. The immortalized pancreatic epithelial cell line HPDE6 was kindly provided by Dr. Stephen Pandol (Veteran's Administration Medical Center, Los Angeles, CA), and all experiments were performed within five passages (15). For primary cultures, freshly resected pancreatic tumors or adjacent normal pancreas tissues were mechanically and enzymatically (trypsin and DNase) disaggregated, and aliquots of tumor cells were seeded in six-well plates. Cell viability was confirmed using a viability kit (Molecular Probes), and keratin staining was used to confirm that >98% of the isolated pancreatic cancer cells were of epithelial origin. Cell aliquots were then incubated in standard DMEM in a range of fetal bovine serum (FBS) concent...

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