Reexamining cancer metabolism: lactate production for carcinogenesis could be the purpose and explanation of the Warburg Effect

Abstract

Herein, we use lessons learned in exercise physiology and metabolism to propose that augmented lactate production ('lactagenesis'), initiated by gene mutations, is the reason and purpose of the Warburg Effect and that dysregulated lactate metabolism and signaling are the key elements in carcinogenesis. Lactate-producing ('lactagenic') cancer cells are characterized by increased aerobic glycolysis and excessive lactate formation, a phenomenon described by Otto Warburg 93 years ago, which still remains unexplained. After a hiatus of several decades, interest in lactate as a player in cancer has been renewed. In normal physiology, lactate, the obligatory product of glycolysis, is an important metabolic fuel energy source, the most important gluconeogenic precursor, and a signaling molecule (i.e. a 'lactormone') with major regulatory properties. In lactagenic cancers, oncogenes and tumor suppressor mutations behave in a highly orchestrated manner, apparently with the purpose of increasing glucose utilization for lactagenesis purposes and lactate exchange between, within and among cells. Five main steps are identified (i) increased glucose uptake, (ii) increased glycolytic enzyme expression and activity, (iii) decreased mitochondrial function, (iv) increased lactate production, accumulation and release and (v) upregulation of monocarboxylate transporters MTC1 and MCT4 for lactate exchange. Lactate is probably the only metabolic compound involved and necessary in all main sequela for carcinogenesis, specifically: angiogenesis, immune escape, cell migration, metastasis and self-sufficient metabolism. We hypothesize that lactagenesis for carcinogenesis is the explanation and purpose of the Warburg Effect. Accordingly, therapies to limit lactate exchange and signaling within and among cancer cells should be priorities for discovery.

Figure 1.

Representation of self-sufficiency in cancer cells. Accelerated glycolysis elicited by oncogenes and tumor suppression mutations depletes nicotinamide adenine dinucleotide (NAD+). The reduction of pyruvate to lactate replenishes cytosolic levels of NAD+ and regulates the status of the equilibrium of the cytoplasmic redox pair (NADH/NAD+) for continuation of glycolysis. Lactate enters mitochondria and is oxidized to pyruvate and then acetyl CoA (A-CoA) through mitochondrial lactate oxidation complex (mLOC) comprised of mitochondrial monocarboxylate transporters (mMCT), its stabilizer, CD147, mitochondrial lactate dehydrogenase (LDH) and cytochrome oxidase (COx). Pyruvate can also enter mitochondria through mitochondrial pyruvate carrier (MPC) for oxidation to A-CoA. In glycolytic cancers, increased glycolysis is chronic which may deplete glycogen stores leading to increased proteolysis for gluconeogenesis, as well as for glutaminolysis to increase cytosolic pyruvate for lactate production. Chronic increased proteolysis for gluconeogenesis and glutaminolysis could explain cachexia in cancer.

Figure 2.

Lactagenesis is a highly orchestrated effort from oncogenes and tumor suppressor mutations for continuous glucose utilization to produce lactate involving five major steps: (i) increased glucose uptake through increased expression and translocation of glucose transporters GLUT by the transcription factors hypoxia-inducible factor 1 (HIF-1) and c-Myc oncogene as well as repression of tumor suppression factor p53 expression; (ii) increased glycolytic enzyme expression and activity, especially Lactate Dehydrogenase A (LDHA) by HIF-1, c-MYC and p53 downregulation; (iii) decreased mitochondrial function mainly by p53 dysregulation; (iv) increased lactate production, accumulation and release due to mass effect of accelerated glycolysis, mitochondrial dysfunction and increased LDHA expression and (v) Upregulation of monocarboxylate transporters MTC1 and MCT4 and their stabilizer, CD147, for lactate export and instigation of carcinogenesis in susceptible cancer candidate cells.

Figure 3.

Lactate is necessary for all the major steps in carcinogenesis; Lactate increases the expression of vascular endothelial growth factor (VEGF) stimulating angiogenesis, increases motility and migration of cancer cells. Lactate is directly involved in the ‘immune escape’ by decreasing monocyte migration and decreased activation of T cells as well as cytokine release and cytotoxic activity. Lactate increases extracellular acidosis of tumor microenvironment decreasing capacity of T-cell to export lactate, thus decreasing T-cell activity. Finally, lactate is necessary for the self-sufficiency of cancer cells by replenishing cytosolic levels of nicotinamide adenine dinucleotide (NAD+) and regulating the status of the equilibrium of the cytoplasmic redox pair (NADH/NAD+) for continuation of glycolysis.

Figure 4.

Proposed mechanisms by which lactagenesis can be halted. Oxamate decreases activity of LDHA and aerobic exercise increases expression of LDHB which oxidizes lactate to pyruvate and may counteract deleterious action of LDHA. Dichloroacetate (DCA) increases the activity of pyruvate dehydrogenase (PDH) which directs glycolytic carbon flux to oxidation and away from lactate production and accumulation. Different inhibitors of MCT1-4 and CD147 are currently being evaluated which would inhibit lactate shuttling between, within and among cancer cells and susceptable candidate cells.