{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T10:24:25Z","timestamp":1779877465132,"version":"3.53.1"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Biosci"],"published-print":{"date-parts":[[2011,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background<\/jats:title>\n            <jats:p>Cancer cells possess unique metabolic phenotypes that are determined by their underlying oncogenic pathways. Activation of the PI3K\/Akt\/mTOR signaling cascade promotes glycolysis and leads to glucose-dependence in tumors. In particular, cells with constitutive mTORC1 activity secondary to the loss of TSC1\/TSC2 function are prone to undergo apoptosis upon glucose withdrawal <jats:italic>in vitro<\/jats:italic>, but this concept has not been tested <jats:italic>in vivo<\/jats:italic>. This study examines the effects of restricting glucose metabolism by pharmacologic and dietary means in a tuberous sclerosis complex (TSC) tumor xenograft model.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Tumor-bearing mice were randomly assigned to receive unrestricted carbohydrate-free (\"Carb-free\") or Western-style diet in the absence or presence of 2-deoxyglucose (2-DG) in one of four treatment groups. After 14 weeks, tumor sizes were significantly different among the four treatment groups with those receiving 2-DG having the smallest tumors. Unexpectedly, the \"Carb-free\" diet was associated with the largest tumors but they remained responsive to 2-DG. PET imaging showed significant treatment-related changes in tumor <jats:sup>18<\/jats:sup>fluorodeoxyglucose-uptake but the standard uptake values did not correlate with tumor size. Alternative energy substrates such as ketone bodies and monounsaturated oleic acid supported the growth of the <jats:italic>Tsc2<\/jats:italic>-\/- cells <jats:italic>in vitro<\/jats:italic>, whereas saturated palmitic acid was toxic. Correspondingly, tumors in the high-fat, \"Carb-free\" group showed greater necrosis and liquefaction that contributed to their larger sizes. In contrast, 2-DG treatment significantly reduced tumor cell proliferation, increased metabolic stress (i.e., ketonemia) and AMPK activity, whereas rapamycin primarily reduced cell size.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our data support the concept of glycolytic inhibition as a therapeutic approach in TSC whereas dietary withdrawal of carbohydrates was not effective.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/2045-3701-1-34","type":"journal-article","created":{"date-parts":[[2011,11,17]],"date-time":"2011-11-17T21:14:45Z","timestamp":1321564485000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Glucose deprivation in tuberous sclerosis complex-related tumors"],"prefix":"10.1186","volume":"1","author":[{"given":"Xiuyun","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heidi L","family":"Kenerson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond S","family":"Yeung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2011,10,21]]},"reference":[{"key":"34_CR1","doi-asserted-by":"publisher","first-page":"1345","DOI":"10.1056\/NEJMra055323","volume":"355","author":"PB Crino","year":"2006","unstructured":"Crino PB, Nathanson KL, Henske EP: The tuberous sclerosis complex. N Engl J Med. 2006, 355: 1345-1356. 10.1056\/NEJMra055323","journal-title":"N Engl J Med"},{"key":"34_CR2","doi-asserted-by":"publisher","first-page":"6008","DOI":"10.1158\/1078-0432.CCR-09-0898","volume":"15","author":"FM Platt","year":"2009","unstructured":"Platt FM, Hurst CD, Taylor CF, Gregory WM, Harnden P: Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. Clin Cancer Res. 2009, 15: 6008-6017. 10.1158\/1078-0432.CCR-09-0898","journal-title":"Clin Cancer Res"},{"key":"34_CR3","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/ng.804","volume":"43","author":"Y Totoki","year":"2011","unstructured":"Totoki Y, Tatsuno K, Yamamoto S, Arai Y, Hosoda F: High-resolution characterization of a hepatocellular carcinoma genome. Nat Genet. 2011, 43: 464-469. 10.1038\/ng.804","journal-title":"Nat Genet"},{"key":"34_CR4","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1186\/1471-2407-8-163","volume":"8","author":"S Chakraborty","year":"2008","unstructured":"Chakraborty S, Mohiyuddin SM, Gopinath KS, Kumar A: Involvement of TSC genes and differential expression of other members of the mTOR signaling pathway in oral squamous cell carcinoma. BMC Cancer. 2008, 8: 163. 10.1186\/1471-2407-8-163","journal-title":"BMC Cancer"},{"key":"34_CR5","doi-asserted-by":"publisher","first-page":"1361","DOI":"10.1016\/j.humpath.2007.01.028","volume":"38","author":"H Kenerson","year":"2007","unstructured":"Kenerson H, Folpe AL, Takayama TK, Yeung RS: Activation of the mTOR pathway in sporadic angiomyolipomas and other perivascular epithelioid cell neoplasms. Hum Pathol. 2007, 38: 1361-1371. 10.1016\/j.humpath.2007.01.028","journal-title":"Hum Pathol"},{"key":"34_CR6","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1002\/path.2289","volume":"214","author":"CC Pan","year":"2008","unstructured":"Pan CC, Chung MY, Ng KF, Liu CY, Wang JS: Constant allelic alteration on chromosome 16p (TSC2 gene) in perivascular epithelioid cell tumour (PEComa): genetic evidence for the relationship of PEComa with angiomyolipoma. J Pathol. 2008, 214: 387-393. 10.1002\/path.2289","journal-title":"J Pathol"},{"key":"34_CR7","doi-asserted-by":"publisher","first-page":"217","DOI":"10.1042\/BST0370217","volume":"37","author":"J Huang","year":"2009","unstructured":"Huang J, Manning BD: A complex interplay between Akt, TSC2 and the two mTOR complexes. Biochem Soc Trans. 2009, 37: 217-222. 10.1042\/BST0370217","journal-title":"Biochem Soc Trans"},{"key":"34_CR8","first-page":"5645","volume":"62","author":"HL Kenerson","year":"2002","unstructured":"Kenerson HL, Aicher LD, True LD, Yeung RS: Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors. Cancer Res. 2002, 62: 5645-5650.","journal-title":"Cancer Res"},{"key":"34_CR9","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1203\/01.PDR.0000147727.78571.07","volume":"57","author":"H Kenerson","year":"2005","unstructured":"Kenerson H, Dundon TA, Yeung RS: Effects of rapamycin in the Eker rat model of tuberous sclerosis complex. Pediatr Res. 2005, 57: 67-75. 10.1203\/01.PDR.0000147727.78571.07","journal-title":"Pediatr Res"},{"key":"34_CR10","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1056\/NEJMoa063564","volume":"358","author":"JJ Bissler","year":"2008","unstructured":"Bissler JJ, McCormack FX, Young LR, Elwing JM, Chuck G: Sirolimus for angiomyolipoma in tuberous sclerosis complex or lymphangioleiomyomatosis. N Engl J Med. 2008, 358: 140-151. 10.1056\/NEJMoa063564","journal-title":"N Engl J Med"},{"key":"34_CR11","doi-asserted-by":"publisher","first-page":"1801","DOI":"10.1056\/NEJMoa1001671","volume":"363","author":"DA Krueger","year":"2010","unstructured":"Krueger DA, Care MM, Holland K, Agricola K, Tudor C: Everolimus for subependymal giant-cell astrocytomas in tuberous sclerosis. N Engl J Med. 2010, 363: 1801-1811. 10.1056\/NEJMoa1001671","journal-title":"N Engl J Med"},{"key":"34_CR12","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.cmet.2007.10.002","volume":"7","author":"RJ DeBerardinis","year":"2008","unstructured":"DeBerardinis RJ, Lum JJ, Hatzivassiliou G, Thompson CB: The biology of cancer: metabolic reprogramming fuels cell growth and proliferation. Cell Metab. 2008, 7: 11-20. 10.1016\/j.cmet.2007.10.002","journal-title":"Cell Metab"},{"key":"34_CR13","doi-asserted-by":"publisher","first-page":"1029","DOI":"10.1126\/science.1160809","volume":"324","author":"MG Vander Heiden","year":"2009","unstructured":"Vander Heiden MG, Cantley LC, Thompson CB: Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009, 324: 1029-1033. 10.1126\/science.1160809","journal-title":"Science"},{"key":"34_CR14","doi-asserted-by":"publisher","first-page":"3892","DOI":"10.1158\/0008-5472.CAN-03-2904","volume":"64","author":"RL Elstrom","year":"2004","unstructured":"Elstrom RL, Bauer DE, Buzzai M, Karnauskas R, Harris MH: Akt stimulates aerobic glycolysis in cancer cells. Cancer Res. 2004, 64: 3892-3899. 10.1158\/0008-5472.CAN-03-2904","journal-title":"Cancer Res"},{"key":"34_CR15","doi-asserted-by":"publisher","first-page":"18782","DOI":"10.1073\/pnas.0810199105","volume":"105","author":"DR Wise","year":"2008","unstructured":"Wise DR, DeBerardinis RJ, Mancuso A, Sayed N, Zhang XY: Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addiction. Proc Natl Acad Sci USA. 2008, 105: 18782-18787. 10.1073\/pnas.0810199105","journal-title":"Proc Natl Acad Sci USA"},{"key":"34_CR16","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1038\/onc.2010.466","volume":"30","author":"N El Mjiyad","year":"2011","unstructured":"El Mjiyad N, Caro-Maldonado A, Ramirez-Peinado S, Munoz-Pinedo C: Sugar-free approaches to cancer cell killing. Oncogene. 2011, 30: 253-264. 10.1038\/onc.2010.466","journal-title":"Oncogene"},{"key":"34_CR17","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/S0092-8674(03)00929-2","volume":"115","author":"K Inoki","year":"2003","unstructured":"Inoki K, Zhu T, Guan KL: TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003, 115: 577-590. 10.1016\/S0092-8674(03)00929-2","journal-title":"Cell"},{"key":"34_CR18","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1016\/j.molcel.2010.05.007","volume":"38","author":"AY Choo","year":"2010","unstructured":"Choo AY, Kim SG, Vander Heiden MG, Mahoney SJ, Vu H: Glucose addiction of TSC null cells is caused by failed mTORC1-dependent balancing of metabolic demand with supply. Mol Cell. 2010, 38: 487-499. 10.1016\/j.molcel.2010.05.007","journal-title":"Mol Cell"},{"key":"34_CR19","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1016\/j.molcel.2010.06.022","volume":"39","author":"K Duvel","year":"2010","unstructured":"Duvel K, Yecies JL, Menon S, Raman P, Lipovsky AI: Activation of a metabolic gene regulatory network downstream of mTOR complex 1. Mol Cell. 2010, 39: 171-183. 10.1016\/j.molcel.2010.06.022","journal-title":"Mol Cell"},{"key":"34_CR20","doi-asserted-by":"publisher","first-page":"1748","DOI":"10.2353\/ajpath.2008.070958","volume":"172","author":"X Jiang","year":"2008","unstructured":"Jiang X, Kenerson H, Aicher L, Miyaoka R, Eary J: The tuberous sclerosis complex regulates trafficking of glucose transporters and glucose uptake. Am J Pathol. 2008, 172: 1748-1756. 10.2353\/ajpath.2008.070958","journal-title":"Am J Pathol"},{"key":"34_CR21","doi-asserted-by":"publisher","first-page":"926","DOI":"10.1378\/chest.09-0336","volume":"136","author":"LR Young","year":"2009","unstructured":"Young LR, Franz DN, Nagarkatte P, Fletcher CD, Wikenheiser-Brokamp KA: Utility of [18F]2-fluoro-2-deoxyglucose-PET in sporadic and tuberous sclerosis-associated lymphangioleiomyomatosis. Chest. 2009, 136: 926-933. 10.1378\/chest.09-0336","journal-title":"Chest"},{"key":"34_CR22","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1007\/s00280-003-0724-7","volume":"53","author":"JC Maher","year":"2004","unstructured":"Maher JC, Krishan A, Lampidis TJ: Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions. Cancer Chemother Pharmacol. 2004, 53: 116-122. 10.1007\/s00280-003-0724-7","journal-title":"Cancer Chemother Pharmacol"},{"key":"34_CR23","doi-asserted-by":"publisher","first-page":"613","DOI":"10.1158\/0008-5472.CAN-04-4313","volume":"65","author":"RH Xu","year":"2005","unstructured":"Xu RH, Pelicano H, Zhou Y, Carew JS, Feng L: Inhibition of glycolysis in cancer cells: a novel strategy to overcome drug resistance associated with mitochondrial respiratory defect and hypoxia. Cancer Res. 2005, 65: 613-621.","journal-title":"Cancer Res"},{"key":"34_CR24","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1007\/s00066-005-1320-z","volume":"181","author":"D Singh","year":"2005","unstructured":"Singh D, Banerji AK, Dwarakanath BS, Tripathi RP, Gupta JP: Optimizing cancer radiotherapy with 2-deoxy-d-glucose dose escalation studies in patients with glioblastoma multiforme. Strahlenther Onkol. 2005, 181: 507-514. 10.1007\/s00066-005-1320-z","journal-title":"Strahlenther Onkol"},{"key":"34_CR25","doi-asserted-by":"publisher","first-page":"462","DOI":"10.1007\/s11883-009-0069-8","volume":"11","author":"CL Boling","year":"2009","unstructured":"Boling CL, Westman EC, Yancy WS: Carbohydrate-restricted diets for obesity and related diseases: an update. Curr Atheroscler Rep. 2009, 11: 462-469. 10.1007\/s11883-009-0069-8","journal-title":"Curr Atheroscler Rep"},{"key":"34_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1146\/annurev.nutr.26.061505.111258","volume":"26","author":"GF Cahill Jr","year":"2006","unstructured":"Cahill GF: Fuel metabolism in starvation. Annu Rev Nutr. 2006, 26: 1-22. 10.1146\/annurev.nutr.26.061505.111258","journal-title":"Annu Rev Nutr"},{"key":"34_CR27","doi-asserted-by":"publisher","first-page":"9154","DOI":"10.1073\/pnas.93.17.9154","volume":"93","author":"F Jin","year":"1996","unstructured":"Jin F, Wienecke R, Xiao GH, Maize JC, DeClue JE: Suppression of tumorigenicity by the wild-type tuberous sclerosis 2 (Tsc2) gene and its C-terminal region. Proc Natl Acad Sci USA. 1996, 93: 9154-9159. 10.1073\/pnas.93.17.9154","journal-title":"Proc Natl Acad Sci USA"},{"key":"34_CR28","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1016\/j.febslet.2010.01.017","volume":"584","author":"CH Jung","year":"2010","unstructured":"Jung CH, Ro SH, Cao J, Otto NM, Kim DH: mTOR regulation of autophagy. FEBS Lett. 2010, 584: 1287-1295. 10.1016\/j.febslet.2010.01.017","journal-title":"FEBS Lett"},{"key":"34_CR29","doi-asserted-by":"publisher","first-page":"S7","DOI":"10.4103\/0973-1482.55134","volume":"1","author":"BT Seyfried","year":"2009","unstructured":"Seyfried BT, Kiebish M, Marsh J, Mukherjee P: Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet. J Cancer Res Ther 5 Suppl. 2009, 1: S7-15.","journal-title":"J Cancer Res Ther 5 Suppl"},{"key":"34_CR30","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1186\/1743-7075-5-33","volume":"5","author":"J Marsh","year":"2008","unstructured":"Marsh J, Mukherjee P, Seyfried TN: Drug\/diet synergy for managing malignant astrocytoma in mice: 2-deoxy-D-glucose and the restricted ketogenic diet. Nutr Metab (Lond). 2008, 5: 33-10.1186\/1743-7075-5-33. 10.1186\/1743-7075-5-33","journal-title":"Nutr Metab (Lond)"},{"key":"34_CR31","doi-asserted-by":"publisher","first-page":"1375","DOI":"10.1038\/sj.bjc.6601269","volume":"89","author":"TN Seyfried","year":"2003","unstructured":"Seyfried TN, Sanderson TM, El-Abbadi MM, McGowan R, Mukherjee P: Role of glucose and ketone bodies in the metabolic control of experimental brain cancer. Br J Cancer. 2003, 89: 1375-1382. 10.1038\/sj.bjc.6601269","journal-title":"Br J Cancer"},{"key":"34_CR32","doi-asserted-by":"publisher","first-page":"557","DOI":"10.1158\/1940-6207.CAPR-08-0188","volume":"2","author":"JC Mavropoulos","year":"2009","unstructured":"Mavropoulos JC, Buschemeyer WC, Tewari AK, Rokhfeld D, Pollak M: The effects of varying dietary carbohydrate and fat content on survival in a murine LNCaP prostate cancer xenograft model. Cancer Prev Res (Phila). 2009, 2: 557-565. 10.1158\/1940-6207.CAPR-08-0188. 10.1158\/1940-6207.CAPR-08-0188","journal-title":"Cancer Prev Res (Phila)"},{"key":"34_CR33","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.braindev.2009.04.009","volume":"32","author":"CJ Chu-Shore","year":"2010","unstructured":"Chu-Shore CJ, Thiele EA: Tumor growth in patients with tuberous sclerosis complex on the ketogenic diet. Brain Dev. 2010, 32: 318-322. 10.1016\/j.braindev.2009.04.009","journal-title":"Brain Dev"},{"key":"34_CR34","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/1475-2867-9-14","volume":"9","author":"EJ Fine","year":"2009","unstructured":"Fine EJ, Miller A, Quadros EV, Sequeira JM, Feinman RD: Acetoacetate reduces growth and ATP concentration in cancer cell lines which over-express uncoupling protein 2. Cancer Cell Int. 2009, 9: 14. 10.1186\/1475-2867-9-14","journal-title":"Cancer Cell Int"},{"key":"34_CR35","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1111\/j.1440-1746.2008.05733.x","volume":"24","author":"M Ricchi","year":"2009","unstructured":"Ricchi M, Odoardi MR, Carulli L, Anzivino C, Ballestri S: Differential effect of oleic and palmitic acid on lipid accumulation and apoptosis in cultured hepatocytes. J Gastroenterol Hepatol. 2009, 24: 830-840. 10.1111\/j.1440-1746.2008.05733.x","journal-title":"J Gastroenterol Hepatol"}],"container-title":["Cell &amp; Bioscience"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/2045-3701-1-34.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T17:03:27Z","timestamp":1630515807000},"score":1,"resource":{"primary":{"URL":"https:\/\/cellandbioscience.biomedcentral.com\/articles\/10.1186\/2045-3701-1-34"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2011,10]]},"references-count":35,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2011,10]]}},"alternative-id":["34"],"URL":"https:\/\/doi.org\/10.1186\/2045-3701-1-34","relation":{},"ISSN":["2045-3701"],"issn-type":[{"value":"2045-3701","type":"electronic"}],"subject":[],"published":{"date-parts":[[2011,10]]},"assertion":[{"value":"3 June 2011","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 October 2011","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 October 2011","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}}],"article-number":"34"}}