Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation

Abstract

In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5′-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.For unicellular organisms such as microbes, there is evolutionary pressure to reproduce as quickly as possible when nutrients are available. Their metabolic control systems have evolved to sense an adequate supply of nutrients and channel the requisite carbon, nitrogen, and free energy into generating the building blocks needed to produce a new cell. When nutrients are scarce, the cells cease biomass production and adapt metabolism to extract the maximum free energy from available resources to survive the starvation period (Fig. 1). Reflecting these fundamental differences in metabolic needs, distinct regulatory mechanisms have evolved to control cellular metabolism in proliferating versus non-proliferating cells.In multicellular organisms, most cells are exposed to a constant supply of nutrients. Survival of the organism requires control systems that prevent aberrant individual cell proliferation when nutrient availability exceeds the levels needed to support cell division. Uncontrolled proliferation is prevented because mammalian cells do not normally take up nutrients from their environment unless stimulated to do so by growth factors. Cancer cells overcome this growth factor dependence by acquiring genetic mutations that functionally alter receptorinitiated signaling pathways. There is growing evidence that some of these pathways constitutively activate the uptake and metabolism of nutrients that both promote cell survival and fuel cell growth (1,2). Oncogenic mutations can result in the uptake of nutrients,

Antifungal compound honokiol triggers oxidative stress responsive signalling pathway and modulates central carbon metabolism

“…Fission yeast is an excellent model for studying fundamental cell behaviours, such as cell growth and proliferation. At the same time, fission yeast displays cancer cell-like metabolic behaviour, called Crabtree effect (similar to the Warburg effect of cancer cell) (Piškur et al 2006; Vander Heiden et al 2009), means it prefers to use fermentation rather than respiration for the energy production. Because of above merits, the mechanism discovery from fission yeast system could be immigrated to clinical medicine feasibly.…”

Aneustat (OMN54) has aerobic glycolysis‐inhibitory activity and also immunomodulatory activity as indicated by a first‐generation PDX prostate cancer model

“…1 d ). As cancer growth greatly relies on aerobic glycolysis,41, 42 the inhibition of aerobic glycolysis by Aneustat could be a major mechanism by which it inhibits the proliferation of LNCaP prostate cancer cells in vitro and in vivo .…”

Vitamin D immunoregulation through dendritic cells

“…However, energy can also be generated without an obligatory need for oxygen through anaerobic glycolysis and consequential excretion of glucose‐derived lactate, useful particularly in relatively anaerobic (hypoxic) environments, as in sites of tissue damage. Rapidly growing tumour cells also show this method of glucose breakdown, but independently of the presence or absence oxygen – then termed aerobic glycolysis, or the Warburg effect 26. The decisive triggers to induce oxidation‐independent Warburg metabolism, and its benefits for a single cell or the organism are still not completely understood 26.…”

“…Rapidly growing tumour cells also show this method of glucose breakdown, but independently of the presence or absence oxygen – then termed aerobic glycolysis, or the Warburg effect 26. The decisive triggers to induce oxidation‐independent Warburg metabolism, and its benefits for a single cell or the organism are still not completely understood 26. Generally, the anabolic needs to synthesize biomolecules during activation, cell division or expansion are supported by Warburg metabolism, converting glucose into carbon donors for fatty acid synthesis or pentose for nucleotide synthesis.…”

“…At the same time, anabolic use of carbon or excretion of lactate rather than oxidative phosphorylation helps to avoid a build up of glycolysis metabolites. This Warburg metabolic pathway has therefore been proposed as a general anabolic principle of activated and proliferating cells, while glucose breakdown through oxidative phosphorylation is a characteristic of differentiated or resting cells – not only for tumours, but also in normal tissue and the immune system 26, 27. Indeed, in murine GM‐CSF‐DC (see below), Toll‐like receptor stimulation promotes increased anabolic glycolysis rather than oxidative phosphorylation, which is crucial for DC activation, survival and function in the face of increased membrane‐forming demands due to secretory processes or migration 28, 29, 30, 31.…”