2-Methoxyestradiol Reverses the Pro-Carcinogenic Effect of L-Lactate in Osteosarcoma 143B Cells

Abstract

Abstract. Background Cancer cells are traditionally characterized by increased glucose uptake, high rates of aerobic glycolysis, increased lactic acid production, impaired mitochondrial function and decreased extracellular pH. These characteristics are known as the 'Warburg effect' (1-3). The 'Warburg effect' is also observed in cancer-associated fibroblasts and mesenchymal stem cells (1-11), which secrete lactate and ketones into the microenvironment of the tumor. Lactic acid exists as L-and D-optical isomers. In mammals including humans, lactate is present almost entirely as L-lactate (12, 13). Interestingly, a variety of human cancer cell lines and human tumors, including breast, prostate, head, neck, and osteosarcoma cancers, import these metabolites and deliver them to the mitochondrial TCA cycle, thereby promoting ATP generation and cell proliferation (1-14). According to this 'reverse Warburg effect', tumor cells can induce metabolic reprogramming by shuttling lactate as an energy source to neighboring cancer cells, to the adjacent stroma and to vascular endothelial cells (1,14).Tumors contain both aerobic and hypoxic regions that form a metabolic symbiosis that is crucial for tumor cell survival (15, 16). The cancer cells located in the hypoxic regions export lactate, which acidifies the tumor environment; the cells located in the aerobic regions, however, import lactate and utilize it for oxidative phosphorylation (4). Bonuccelli and colleagues (2) suggested that L-lactate metabolism in cancer cells may explain why diabetic patients have an increased risk of cancer development and a tendency towards autophagy/mitophagy in their adipose tissue. An increased tumor L-lactate level strictly correlates with increased metastasis, tumor recurrence and poor outcome (6-9).L-lactate metabolism and the reverse Warburg effect has been clearly established in osteosarcoma cells. It has been demonstrated that the secretion of lactate and ketones by the mesenchymal stem cells drives mitochondrial biogenesis and increases the mitochondrial activity in osteosarcoma cells (1, 483 This article is freely accessible online.Correspondence to: Magdalena Gorska-Ponikowska (MGP),

Regulation of mitochondrial dynamics in 2-methoxyestradiol-mediated osteosarcoma cell death

“…We further proved that 2-ME at both physiologically and pharmacologically relevant concentrations inhibited OS cell proliferation and migration due to regulation of mitochondrial biogenesis 22 . We also observed the induction of autophagy by 2-ME in OS cells 23 .…”

“…OS 143B cells were cultured at 37˚C in a humidified atmosphere, saturated with 5% CO 2 . Minimum Essential Medium Eagle (MEM) was supplemented with 2 mM glutamine, 1% nonessential amino acids, and 10% heat-inactivated fetal bovine serum (FBS) 23 . In order to avoid the effects of glucose and Warburg effect in OS cells, low glucose, pyruvate and lactate-free MEM was chosen for cell culture and treatment 23 .…”

Lactate in Sarcoma Microenvironment: Much More than just a Waste Product

“…We have already mentioned the correlation between lactate and reverse Warburg in OS cells, as shown by Bonuccelli G et al Gorska-Ponikowska M. et al showed that lactate administration induces both proliferation and migration of OS HOS-143B cells, while a potent anticancer agent, namely 2-methoxyestradiol (2-ME), currently under investigation in clinical trials for treatment of OS, breast and prostate carcinomas, is able to reverse these effects [156]. In particular, through the generation of nitro-oxidative stress and by inhibiting the mitochondrial respiratory complex I, 2-ME repressed lactate-induced cancer cell migration and promoted apoptosis in OS cells [156].…”

2-Methoxyestradiol in Pulmonary Arterial Hypertension: A New Disease Modifier

“…Presently, the effects of 2ME on metabolic reprograming in PAH are unknown. However, 2ME inhibits lactate-induced mitochondrial biogenesis in highly proliferative osteosarcoma cells, and in apoptosis-resistant melanoma cells, 2ME attenuates proliferation and glycolysis by inhibiting HIF-1α and PDK expression [113][114][115]. Therefore, 2ME could be viewed as modulator of metabolic reprograming.…”