The Warburg effect drives cachectic states in patients with pancreatobiliary adenocarcinoma.
cancer cachexia
nude mice
pancreatobiliary adenocarcinoma
patients
the Warburg effect
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
09 2023
09 2023
Historique:
revised:
21
07
2023
received:
04
04
2023
accepted:
03
08
2023
medline:
17
8
2023
pubmed:
16
8
2023
entrez:
16
8
2023
Statut:
ppublish
Résumé
We have studied whether the Warburg effect (uncontrolled glycolysis) in pancreatobiliary adenocarcinoma triggers cachexia in the patient. After 74 pancreatobiliary adenocarcinomas were removed by surgery, their glucose transporter-1 and four glycolytic enzymes were quantified using Western blotting. Based on the resulting data, the adenocarcinomas were equally divided into a group of low glycolysis (LG) and a group of high glycolysis (HG). Energy homeostasis was assessed in these cancer patients and in 74 non-cancer controls, using serum albumin and C-reactive protein and morphometrical analysis of abdominal skeletal muscle and fat on computed tomography scans. Some removed adenocarcinomas were transplanted in nude mice to see their impacts on host energy homeostasis. Separately, nude mice carrying tumor grafts of MiaPaCa-2 pancreatic adenocarcinoma cells were treated with the glycolytic inhibitor 3-bromopyruvate and with emodin that inhibited glycolysis by decreasing hypoxia-inducible factor-1α. Adenocarcinomas in both group LG and group HG impaired energy homeostasis in the cancer patients, compared to the non-cancer reference. The impaired energy homeostasis induced by the adenocarcinomas in group HG was more pronounced than that by the adenocarcinomas in group LG. When original adenocarcinomas were grown in nude mice, their glycolytic abilities determined the levels of hepatic gluconeogenesis, skeletal muscle proteolysis, adipose-tissue lipolysis, and weight loss in the mice. When MiaPaCa-2 cells were grown as tumors in nude mice, 3-bromopyruvate and emodin decreased tumor-induced glycolysis and cachexia, with the best effects being seen when the drugs were administered in combination. In conclusion, the Warburg effect in pancreatobiliary adenocarcinoma triggers cancer cachexia.
Identifiants
pubmed: 37584661
doi: 10.1096/fj.202300649R
doi:
Substances chimiques
bromopyruvate
63JMV04GRK
Emodin
KA46RNI6HN
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e23144Informations de copyright
© 2023 Federation of American Societies for Experimental Biology.
Références
Petruzzelli M, Wagner EF. Mechanisms of metabolic dysfunction in cancer-associated cachexia. Genes Dev. 2016;30:489-501.
Tisdale MJ. Biology of cachexia. J Natl Cancer Inst. 1997;89:1763-1773.
Baba MR, Buch SA. Revisiting cancer cachexia: pathogenesis, diagnosis, and current treatment approaches. Asia Pac J Oncol Nurs. 2021;8:508-518.
Muliawati Y, Haroen H, Rotty LW. Cancer anorexia - cachexia syndrome. Acta Med Indones. 2012;44:154-162.
Martignoni ME, Kunze P, Hildebrandt W, et al. Role of mononuclear cells and inflammatory cytokines in pancreatic cancer-related cachexia. Clin Cancer Res. 2005;11:5802-5808.
Todorov PT, McDevitt TM, Meyer DJ, Ueyama H, Ohkubo I, Tisdale MJ. Purification and characterization of a tumor lipid-mobilizing factor. Cancer Res. 1998;58:2353-2358.
Todorov PT, Field WN, Tisdale MJ. Role of a proteolysis-inducing factor (PIF) in cachexia induced by a human melanoma (G361). Br J Cancer. 1999;80:1734-1737.
Warburg O, Wind F, Negelein E. The metabolism of tumors in the body. J Gen Physiol. 1927;8:519-530.
Crabtree HG. Observations on the carbohydrate metabolism of tumours. Biochem J. 1929;23:536-545.
Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.
Liu Z, Jia X, Duan Y, et al. Excess glucose induces hypoxia-inducible factor-1α in pancreatic cancer cells and stimulates glucose metabolism and cell migration. Cancer Biol Ther. 2013;14:428-435.
Holroyde CP, Gabuzda TG, Putnam RC, Paul P, Reichard GA. Altered glucose metabolism in metastatic carcinoma. Cancer Res. 1975;35:3710-3714.
Lundholm K, Edström S, Karlberg I, Ekman L, Scherstén T. Glucose turnover, gluconeogenesis from glycerol, and estimation of net glucose cycling in cancer patients. Cancer. 1982;50:1142-1150.
Edén E, Edström S, Bennegård K, Scherstén T, Lundholm K. Glucose flux in relation to energy expenditure in malnourished patients with and without cancer during periods of fasting and feeding. Cancer Res. 1984;44:1718-1724.
Burt ME, Lowry SF, Gorschboth C, Brennan MF. Metabolic alterations in a noncachectic animal tumor system. Cancer. 1981;47:2138-2146.
Torosian MH, Bartlett DL, Chatzidakis C, Stein TP. Effect of tumor burden on futile glucose and lipid cycling in tumor-bearing animals. J Surg Res. 1993;55:68-73.
Hu L, Cui R, Liu H, Wang F. Emodin and rhein decrease hypoxia-inducible factor-1α in human pancreatic cancer cells and attenuate cancer cachexia in athymic mice carrying the cancer cells. Oncotarget. 2017;8:88008-88020.
Yang J, Wang F, Chen X, Qiu S, Cui L, Hu L. β-Pentagalloyl-glucose sabotages pancreatic cancer cells and ameliorates cachexia in tumor-bearing mice. Am J Chin Med. 2019;47:675-689.
Wang F, Li SS, Segersvärd R, et al. Hypoxia inducible factor-1 mediates effects of insulin on pancreatic cancer cells and disturbs host energy homeostasis. Am J Pathol. 2007;170:469-477.
Wang F, Liu H, Hu L, et al. The Warburg effect in human pancreatic cancer cells triggers cachexia in athymic mice carrying the cancer cells. BMC Cancer. 2018;18:360.
Hu L, Xu X, Li Q, et al. Caveolin-1 increases glycolysis in pancreatic cancer cells and triggers cachectic states. FASEB J. 2021;35:e21826.
Feng J, Li J, Wu L, et al. Emerging roles and the regulation of aerobic glycolysis in hepatocellular carcinoma. J Exp Clin Cancer Res. 2020;39:126.
Hu L, Chen X, Qiu S, et al. Intra-pancreatic insulin nourishes cancer cells: do insulin-receptor antagonists such as PGG and EGCG play a role? Am J Chin Med. 2020;48:1005-1019.
Fan T, Sun G, Sun X, Zhao L, Zhong R, Peng Y. Tumor energy metabolism and potential of 3-bromopyruvate as an inhibitor of aerobic glycolysis: implications in tumor treatment. Cancers (Basel). 2019;11:317.
Xiao H, Li S, Zhang D, Liu T, Yu M, Wang F. Separate and concurrent use of 2-deoxy-D-glucose and 3-bromopyruvate in pancreatic cancer cells. Oncol Rep. 2013;29:329-334.
Shrimali D, Shanmugam MK, Kumar AP, et al. Targeted abrogation of diverse signal transduction cascades by emodin for the treatment of inflammatory disorders and cancer. Cancer Lett. 2013;341:139-149.
Sang-Yhun J, Ma S-J. High C-reactive protein to albumin ratio and the short-term survival prognosis within 30 days in terminal cancer patients receiving palliative care in a hospital setting: a retrospective analysis. Medicine (Baltimore). 2020;99:e19350.
Jabłońska B, Pawlicki K, Mrowiec S. Associations between nutritional and immune status and clinicopathologic factors in patients with pancreatic cancer: a comprehensive analysis. Cancers (Basel). 2021;13:5041.
Barker T, Fulde G, Moulton B, Nadauld LD, Rhodes T. An elevated neutrophil-to-lymphocyte ratio associates with weight loss and cachexia in cancer. Sci Rep. 2020;10:7535.
Babic A, Rosenthal MH, Bamlet WR, et al. Postdiagnosis loss of skeletal muscle, but not adipose tissue, is associated with shorter survival of patients with advanced pancreatic cancer. Cancer Epidemiol Biomarkers Prev. 2019;28:2062-2069.
Martin L, Birdsell L, Macdonald N, et al. Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index. J Clin Oncol. 2013;31:1539-1547.
Saeed U, Myklebust TÅ, Robsahm TE, et al. Body mass index and pancreatic adenocarcinoma: a nationwide registry-based cohort study. Scand J Surg. 2023;112:11-21.
Zhang D, Cui L, Li S, Wang F. Insulin and hypoxia-inducible factor-1 cooperate in pancreatic cancer cells to increase cell viability. Oncol Lett. 2015;10:1545-1550.
Mu W, Katsoulakis E, Whelan CJ, Gage KL, Schabath MB, Gillies RJ. Radiomics predicts risk of cachexia in advanced NSCLC patients treated with immune checkpoint inhibitors. Br J Cancer. 2021;125:229-239.
Olaechea S, Gannavarapu BS, Alvarez C, et al. Primary tumor fluorine-18 fluorodeoxydglucose (18F-FDG) is associated with cancer-associated weight loss in non-small cell lung cancer (NSCLC) and portends worse survival. Front Oncol. 2022;12:900712.
Olaechea S, Gannavarapu BS, Gilmore A, Alvarez C, Iyengar P, Infante R. The influence of tumour fluorodeoxyglucose avidity and cachexia development on patient survival in oesophageal or gastroesophageal junction cancer. JCSM Clin Rep. 2021;6:128-136.
Vudatha V, Devarakonda T, Liu C, et al. Review of mechanisms and treatment of cancer-induced cardiac cachexia. Cell. 2022;11:1040.
Khorasanchi A, Nemani S, Pandey S, Del Fabbro E. Managing nutrition impact symptoms in cancer cachexia: a case series and mini review. Front Nutr. 2022;9:831934.
Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992;12:5447-5454.
Khan MA, Zubair H, Anand S, Srivastava SK, Singh S, Singh AP. Dysregulation of metabolic enzymes in tumor and stromal cells: role in oncogenesis and therapeutic opportunities. Cancer Lett. 2020;473:176-185.
Hu L, Xu X, Chen X, et al. Epigallocatechin-3-gallate decreases hypoxia-inducible factor-1 in pancreatic cancer cells. Am J Chin Med. 2023;51:761-777.
Vallée A, Lecarpentier Y, Vallée JN. The key role of the WNT/β-catenin pathway in metabolic reprogramming in cancers under normoxic conditions. Cancers (Basel). 2021;13:5557.
Xia P, Zhang H, Lu H, et al. METTL5 stabilizes c-Myc by facilitating USP5 translation to reprogram glucose metabolism and promote hepatocellular carcinoma progression. Cancer Commun (Lond). 2023;43:338-364.
Nie Z, Hu G, Wei G, et al. c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell. 2012;151:68-79.
Patange S, Ball DA, Wan Y, et al. MYC amplifies gene expression through global changes in transcription factor dynamics. Cell Rep. 2022;38:110292.
Podar K, Anderson KC. A therapeutic role for targeting c-Myc/Hif-1-dependent signaling pathways. Cell Cycle. 2010;9:1722-1728.
Cui J, Jiang H. Prediction of postoperative survival of triple-negative breast cancer based on nomogram model combined with expression of HIF-1α and c-myc. Medicine (Baltimore). 2019;98:e17370.
Boldrini L, Bartoletti R, Giordano M, et al. C-Myc, HIF-1α, ERG, TKT, and GSTP1: an axis in prostate cancer? Pathol Oncol Res. 2019;25:1423-1429.
Liu X, Zhou Y, Peng J, Xie B, Shou Q, Wang J. Silencing c-Myc enhances the antitumor activity of bufalin by suppressing the HIF-1α/SDF-1/CXCR4 pathway in pancreatic cancer cells. Front Pharmacol. 2020;11:495.
Ding X, Zhou X, Jiang B, Zhao Q, Zhou G. Triptolide suppresses proliferation, hypoxia-inducible factor-1α and c-Myc expression in pancreatic cancer cells. Mol Med Rep. 2015;12:4508-4513.
Chen T, Li K, Liu Z, et al. WDR5 facilitates EMT and metastasis of CCA by increasing HIF-1α accumulation in Myc-dependent and independent pathways. Mol Ther. 2021;29:2134-2150.
Bellance N, Lestienne P, Rossignol R. Mitochondria: from bioenergetics to the metabolic regulation of carcinogenesis. Front Biosci. 2009;14:4015-4034.
Selak MA, Armour SM, MacKenzie ED, et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase. Cancer Cell. 2005;7:77-85.
Chen Z, Zhang H, Lu W, Huang P. Role of mitochondria- associated hexokinase II in cancer cell death induced by 3-bromopyruvate. Biochim Biophys Acta. 2009;1787:553-560.