Mouse Astrocytes are Able to Regulate Energy Metabolism Through the Warburg Effect Similar to Cancer Cells

Document Type : Original Article


1 MSC Student of Clinical Biochemistry.Department of Clinical Biochemistry, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.

2 MSc of Clinical Biochemistry.Abadan School of Medical Sciences, Abadan, Iran

3 Assistant Professor of Clinical Biochemistry.Department of Clinical Biochemistry, Cellular and Molecular Research Center, School of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.


Background and Objective: In Warburg effect, an aerobic glycolysis, tumor cells tend to absorb glucose and secrete lactate in the presence of oxygen to provide the energy needed for the growth in nutrient-poor conditions. Previous studies have shown that fetal cells behave like cancer cells. Based on those researches, we examined the Warburg effect in cultured fetal astrocytes isolated from the newborn mouse brain of C57BL/6 by creating a condition similar to cancer cells to induce cell starvation.
Subjects and Methods: Astrocytes were cultured in DMEM/ FBS 10% and starvation was induced during the subculture for the period of 16, 48 and 72 hr.  At the end glucose, lactate secretion and intracellular LDH activity were measured by a colorimetric method.
Results: Glucose consumption was increased to 42% after 48 hr of starvation (P< 0.05). Starvation-mediated events indicate an increase of lactate release after 16 hr and a significant increase in intracellular LDH activity by 7.63 fold after 72 hr compared to the control (P< 0.05).
Conclusion: Lactate production and secretion acts as a necessary source of energy and also a chemical component for signaling to other cells similar to what happen in the tumor cells. Since we provided a condition like tumor cells environment for astrocytes, it is concluded that astrocetes, like other cells, can mimic Warburg effect and this lead to a better understanding of tumor cell metabolism concepts to design of novel therapeutic strategies to target these cells in the brain.


1-Sofroniew MV, Vinters HV. Astrocytes: biology and pathology. Acta neuropathologica. 2010;119(1):7-35. 
2-Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: the revolution continues. Nat Rev Neurosci. 2005;6(8):626-40.
3-Fonnum F. Glutamate: a neurotransmitter in mammalian brain. Journal of neurochemistry. 1984;42(1):1-11.
4-Nedergaard M, Ransom B, Goldman SA. New roles for astrocytes: redefining the functional architecture of the brain. Trends in neurosciences. 2003;26(10):523-30.
5-Koehler RC, Roman RJ, Harder DR. Astrocytes and the regulation of cerebral blood flow. Trends in neurosciences. 2009;32(3):160-9.
6-Wolf F, Kirchhoff F. Imaging Astrocyte Activity. Science. 2008;320(5883):1597-9 .
7-Pellerin L, Bouzier-Sore AK, Aubert A, Serres S, Merle M, Costalat R, et al. Activity-dependent regulation of energy metabolism by astrocytes: an update. Glia. 2007;55(12):1251-62.
8-Lorger M. Tumor microenvironment in the brain. Cancers. 2012;4(1):218-43.
9-Sotgia F, Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Lisanti MP. Understanding the Warburg effect and the prognostic value of stromal caveolin-1 as a marker of a lethal tumor microenvironment. Breast Cancer Research. 2011;13(4):1-13.
10-Tripathi M, Billet S, Bhowmick NA. Understanding the role of stromal fibroblasts in cancer progression. Cell adhesion & migration. 2012;6(3):231-5.
11-Ronnov-Jessen L, Petersen OW, Bissell MJ. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiological reviews. 1996;76(1):69-125.
12-Mueller-Klieser W, Walenta S, Paschen W, Kallinowski F, Vaupel P. Metabolic imaging in microregions of tumors and normal tissues with bioluminescence and photon counting.Journal of the National Cancer Institute. 1988;80(11):842-8.
13-Vaupel P, Kallinowski F, Okunieff P. Blood flow, oxygen and nutrient supply, and metabolic microenvironment of human tumors: a review. Cancer research. 1989;49(23):6449-65.
14-Baek JH, Jang JE, Kang CM, Chung HY, Kim ND, Kim KW. Hypoxia-induced VEGF enhances tumor survivability via suppression of serum deprivation-induced apoptosis. Oncogene. 2000;19(40):4621-31.
15-Dang CV, Semenza GL. Oncogenic alterations of metabolism. Trends in biochemical sciences. 1999;24(2):68-72.
16-Bae SK, Baek JH, Lee YM, Lee OH, Kim KW. Hypoxia-induced apoptosis in human hepatocellular carcinoma cells: a possible involvement of the 6-TG-sensitive protein kinase(s)-dependent signaling pathway. Cancer letters. 1998;126(1):97-104.
17-Warburg O. On the origin of cancer cells. Science. 1956;123(3191):309-14.
18-Dang CV. PKM2 tyrosine phosphorylation and glutamine metabolism signal a different view of the Warburg effect. Science signaling. 2009;2(97):pe75.
19-Lisanti MP, Martinez-Outschoorn UE, Chiavarina B, Pavlides S, Whitaker-Menezes D, Tsirigos A, et al. Understanding the "lethal" drivers of tumor-stroma co-evolution: emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment. Cancer biology & therapy. 2010;10(6):537-42.
20-Lu H, Forbes RA, Verma A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis. The Journal of biological chemistry. 2002;277(26):23111-5.
21-Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nature reviews Cancer. 2011;11(2):85-95.
22-Deberardinis RJ, Sayed N, Ditsworth D, Thompson CB. Brick by brick: metabolism and tumor cell growth. Current opinion in genetics & development. 2008;18(1):54-61.
23-Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134(5):703-7.
24-Rattigan YI, Patel BB, Ackerstaff E, Sukenick G, Koutcher JA, Glod JW, et al. Lactate is a mediator of metabolic cooperation between stromal carcinoma associated fibroblasts and glycolytic tumor cells in the tumor microenvironment. Experimental cell research. 2012;318(4):326-35.
25-Ito J-i, Nagayasu Y, Lu R, Kheirollah A, Hayashi M, Yokoyama S. Astrocytes produce and secrete FGF-1, which promotes the production of apoE-HDL in a manner of autocrine action. Journal of Lipid Research. 2005;46(4):679-86.
26-Philp A, Macdonald AL, Watt PW. Lactate--a signal coordinating cell and systemic function. The Journal of experimental biology. 2005;208(Pt 24):4561-75.
27-Lemons JM, Feng X-J, Bennett BD, Legesse-Miller A, Johnson EL, Raitman I, et al. Quiescent fibroblasts exhibit high metabolic activity. PLoS Biol. 2010;8(10):e1000514.
28-Golpour M, Akhavan Niaki H, Khorasani HR, Hajian A, Mehrasa R, Mostafazadeh A. Human fibroblast switches to anaerobic metabolic pathway in response to serum starvation: a mimic of Warburgeffect.International journal of molecular and cellular medicine. 2014;3(2):74-80.
29-Wu CA, Chao Y, Shiah SG, Lin WW. Nutrient deprivation induces the Warburg effect through ROS/AMPK-dependent activation of pyruvate dehydrogenase kinase. Biochimica et biophysica acta. 2013;1833(5):1147-56.