Abstract
Tumor cells must generate sufficient ATP and biosynthetic precursors in order to maintain cell proliferation requirements. Otto Warburg showed that tumor cells uptake high amounts of glucose producing large volumes of lactate even in the presence of oxygen, this process is known as “Warburg effect or aerobic glycolysis.” As a consequence of such amounts of lactate there is an acidification of the extracellular pH in tumor microenvironment, ranging between 6.0 and 6.5. This acidosis favors processes such as metastasis, angiogenesis and more importantly, immunosuppression, which has been associated to a worse clinical prognosis. Thus, lactate should be thought as an important oncometabolite in the metabolic reprogramming of cancer. In this review, we summarized the role of lactate in regulating metabolic microenvironment of cancer and discuss its relevance in the up-regulation of the enzymes lactate dehydrogenase (LDH) and monocarboxilate transporters (MCTs) in tumors. The goal of this review is to expose that lactate is not only a secondary product of cellular metabolic waste of tumor cells, but also a key molecule involved in carcinogenesis as well as in tumor immune evasion. Finally, the possible targeting of lactate production in cancer treatment is discussed.
Highlights
Cellular transformation involves the deregulated control of cell proliferation, resistance to cell death, immune evasion and circumvention of growth suppressor activities, which allow cancer establishment [1]
FX11 effectively inhibited tumor growth in xenografts derived from both cell lines; the combination of FX11 with FK866 induced tumor regression in the human lymphoma xenograft model. These results showed that LDHA is required for tumor progression where targeting cancer metabolism using small molecules provides a manner for controlling tumor growth
The pharmacological and genetic inhibition of LDHA re-sensitized the TAM-resistant breast cancer cells to tamoxifen, and inhibited the autophagy process increasing cell death. These results provided a link between LDHA and Beclin-1, an important regulator of autophagy, in the induction of the cytoprotective autophagy of TAM-resistant breast cancer cells
Summary
Cellular transformation involves the deregulated control of cell proliferation, resistance to cell death, immune evasion and circumvention of growth suppressor activities, which allow cancer establishment [1]. It has been observed that tumor cells have the remarkable ability to adjust their energetic metabolism as part of their mechanisms for tumor survival, this feature is recognized as a hallmark of cancer [2]. The increased metabolic rate in several neoplasms, was first studied by Otto Warburg in 1926 demonstrating that tumor cells uptake high amounts of glucose as a primary energy source, producing excessive amounts of lactate, even in the presence of oxygen [3]. It was proposed that the driving event of the enhanced glycolysis in tumor cells was caused by an irreversible damage of the mitochondrial function. Defects in mitochondria function have been shown in some types of cancer [5], this process alone cannot explain the metabolic preference of tumor cells
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