Biochemical and Biophysical Research Communications
Lactic acid induces lactate transport and glycolysis/OXPHOS interconversion in glioblastoma
Introduction
Most tumor cells use glycolysis rather than oxidative phosphorylation (OXPHOS) as the main energy metabolic pathway to produce ATP. Although glycolysis is far less efficient than OXPHOS for ATP generation, tumor cells display abnormally high glycolytic rates in order to preserve high ATP levels [1,2]. The excessive conversion of glucose to lactate, even with ample oxygen in tumor cells, is called the Warburg effect [3].
As a consequence of heightened glycolysis, lactate levels can be up to 40 mM in tumors; otherwise, the physiological concentration of lactate is between 1.8 mM and 2 mM in normal tissue [4]. Hence, lactic acidosis generally exists in solid tumor microenvironments. High levels of lactic acid were initially considered to be merely an indicator of the glycolytic flux. However, some evidence has indicated that lactic acid may directly contribute to tumor growth, metastasis and angiogenesis [5]. Besides, clinical studies have demonstrated that patients with high levels of lactate showed poor prognoses and bad overall survival rates of head and neck cancer and non-small cell lung cancer [6,7].
Additionally, due to rapid proliferation, disorganized vasculature and dysfunctional capillary, glucose deprivation is also a common condition in most solid tumors. Hence, lactic acidosis and glucose deprivation are the common adverse microenvironments in solid tumors [8]. In vitro, tumor cells undergo apoptosis when tumor cells are cultured in a glucose-deprived medium [9]. However, solid tumors plainly resist glucose deprivation in vivo. This indicates that the tumor microenvironment may contain factors that allow cancer cells to resist glucose deprivation-induced apoptosis. Hui et al. have reported that tumors can use lactate as a fuel in lung tumors and the contribution of lactate to the TCA cycle in vivo exceeds that of glucose [10]. High concentrations of lactic acid may provide a necessary fuel source for glucose-deprived tumors to avoid apoptosis.
Recent reports have also shown that the Warburg effect, the hallmark of tumors, is variable. The metabolic pathway of tumor cells can be affected by the tumor microenvironment [11]. So, apart from its use as a fuel, it remains unclear whether lactic acid may be able to induce a change in the energy metabolic pathways of tumor cells and how tumor cells could more efficiently utilize lactic acid to adapt to adverse microenvironments.
Glioblastoma (GBM), the most common and malignant brain cancer, is characterized by prominent cellular heterogeneity, high-speed proliferation, extensive invasion of brain tissue and almost inevitable recurrence [12]. Prior studies have reported that malignant brain tumors show intensive glycolysis, lactic acidosis and glucose deprivation [12]. Glioblastoma may be a preferable material in which to explore the role of lactic acid in the tumor microenvironment. Hence, under glucose-deprived conditions, U251 was treated with lactic acid. We subsequently detected a change in the cell cycle, cell growth, cell ATP content and the relative abundance of metabolic molecules.
This research will be of significance in understanding the metabolic mechanism used by tumor cells to survive and resist adverse microenvironments, which could contribute to the clinical treatment of GBM.
Section snippets
Cell lines, cell culture and reagents
U251 cell line was purchased from the Kunming cell bank of the Chinese Academy of Science. The cells were cultured at 37 °C, 5% CO2 in high glucose Dulbecco's modified Eagle's medium (DMEM, Gibco) supplemented with 10% fetal bovine serum (FBS, BI), 100 U/ml penicillin (Gibco) and 100 U/ml streptomycin (Gibco).
Tumor samples
Glioblastoma tissue samples were collected during surgical procedures at the Department of Pathology, the People's Hospital of Dali (Dali, China). These samples were composed of
Lactic acid promotes cell growth and increases ATP levels in U251 cells
Proliferated tumor cells are characterized by the Warburg effect. As an outcome of the high rate of glycolysis, lactic acidosis is a common condition in solid tumors. To explore the energy metabolic change in U251 cells, which exhibit a classical Warburg effect under lactic acidosis [13], we treated U251 cells with 0–30 mM lactic acid for 48 h. The results showed that under lactic acidosis, especially in the 15-mM lactic acid condition, the cell growth was significantly increased, and the ATP
Discussion
In the last century, Otto Warburg proposed that tumor cells depend on glycolysis and glycolysis is the main source of energy in both aerobic and anaerobic conditions [3]. The increase in glucose uptake and the enhancement of glycolysis is a metabolic hallmark of tumor cells [14]. Hypoxia-inducible factor 1 (HIF-1) is the most important regulation molecular for up-regulating glycolysis [15]. It can inhibit glucose carbon to flow into the TCA cycle and accelerate the conversion of pyruvate into
Conflict of interest
None.
Acknowledgements
All work in this manuscript was financially supported by the National Natural Science Foundation of China (no. 31760331, 31260276, 31160237, 81271330, 81360310, 31106237, 31471187, 31171215, 31601155) and Yunnan Province Science and Technology Innovation Team (2011CI123).
References (23)
- et al.
Hallmarks of cancer: the next generation
Cell
(2011) - et al.
Lactate: mirror and motor of tumor malignancy
Semin. Radiat. Oncol.
(2004) - et al.
Elevated tumor lactate concentrations predict for an increased risk of metastases in head-and-neck cancer
Int. J. Radiat. Oncol. Biol. Phys.
(2001) - et al.
HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation
Canc. Cell
(2007) - et al.
HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption
Cell Metabol.
(2006) - et al.
HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia
Cell Metabol.
(2006) - et al.
HIF-1 inhibits mitochondrial biogenesis and cellular respiration in VHL-deficient renal cell carcinoma by repression of C-MYC activity
Canc. Cell
(2007) - et al.
MCT4 defines a glycolytic subtype of pancreatic cancer with poor prognosis and unique metabolic dependencies
Cell Rep.
(2014) - et al.
Glucose metabolism in cancer cells
Curr. Opin. Clin. Nutr. Metab. Care
(2010) On the origin of cancer cells
Science
(1956)
Multiple biological activities of lactic acid in cancer: influences on tumor growth, angiogenesis and metastasis
Curr. Pharmaceut. Des.
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Authors contributed equally.