The Living Force
True. Fatty acids seem to be a major source of energy for many cancers. It seems that cancer cells will burn whatever is available.Macias was actually highly critical of the research done by D'Agostino. He very convincingly discussed the shortcomings of the research, and he brought up the fact that treating cancer with diets is not so clear cut. There are cancers that apparently can use ketones/ fatty acids as their fuel.]
When you consider Gerson therapy (which supposedly had great results), it limited most fats and animal products from the diet and focused primarily on nutrients and juices. So many factors appear to be at play.
Here's a paper I read some months ago on fatty acid oxidation in cancer cells:
Cancer metabolism: fatty acid oxidation in the limelight
Warburg suggested that the alterations in metabolism that he observed in cancer cells were due to the malfunction of mitochondria. In the past decade, we have revisited this idea and reached a better understanding of the ‘metabolic switch’ in cancer cells, including the intimate and causal relationship between cancer genes and metabolic alterations, and their potential to be targeted for cancer treatment. However, the vast majority of the research into cancer metabolism has been limited to a handful of metabolic pathways, while other pathways have remained in the dark. This Progress article brings to light the important contribution of fatty acid oxidation to cancer cell function.
The process of cellular transformation and cancer progression involves genetic mutations and epigenetic alterations, as well as the rewiring of cellular signalling and the reprogramming of metabolic pathways1. We now perceive these processes as intimately interconnected and interdependent2. Emanating from the initial hypothesis of Warburg3 (now known as Warburg's hypothesis), the latest research has revealed that metabolic reprogramming occurs as a consequence of mutations in cancer genes and alterations in cellular signalling. Much of the hype in cancer metabolism comes from the genuine observation that most cancer cells are programmed to increase glucose uptake, but to reduce the proportion of glucose oxidized in the Krebs cycle. Rather than oxidizing glucose for ATP production, glucose in cancer cells tends to be used for anabolic processes, such as ribose production, protein glycosylation and serine synthesis4–7. Cancer cells use additional nutritional inputs for anabolism besides glucose. From its metabolism to pyruvate, glutamine is key for providing reduced NADPH, which is needed for lipid synthesis, and to refill the Krebs cycle (anaplerosis)8,9. The control of this pathway by key oncogenes, such as MYC and mutant RAS, has further enforced the importance of this route in cancer. This view of cancer metabolism takes the focus away from ATP as the key product of glucose and glutamine catabolism. The fact is that in most biological contexts (but not all, as we discuss below), ATP production is sufficient for cancer cell function.
In addition to glucose and glutamine, fatty acids are an extremely relevant energy source. They can be incorporated from the extracellular media, or can be potentially obtained from hydrolysed triglycerides (in cells accumulating lipid droplets) by neutral (N) hydrolases in the cytoplasm or acid (A) hydrolases through a novel autophagic pathway: lipophagy10. De novo synthesis of fatty acids is required for membrane synthesis and therefore for cell growth and proliferation. Fatty acid synthesis is an anabolic process that starts from the conversion of acetyl CoA to malonyl CoA by acetyl CoA carboxylase. Malonyl CoA is then committed to fatty acid synthesis (FAS) and is involved in the elongation of fatty acids through fatty acid synthase (FASN). Additional modifications of fatty acids can be carried out by elongases and desaturases. Fatty acids are catabolized by the fatty acid oxidation (FAO; also known as β-oxidation) pathway.
With most cancer researchers focusing on glycolysis, glutaminolysis and fatty acid synthesis, the relevance of FAO for cancer cell function has not been carefully examined, and its relevance has remained obscure. However, studies in the past 4 years have started to bring to light a relevant role for this metabolic pathway in cancer, and this is accompanied by new and exciting therapeutic implications. The focus of this Progress article is to enumerate, highlight and integrate these recent findings into our current understanding of metabolic reprogramming in cancer cells.
Extra ATP when needed
Relative to their dry mass, fatty acids provide twice as much ATP as carbohydrates (six times more when comparing stored fatty acids to stored glycogen), and in turn they are the preferred nutrient for storage (in the form of triglycerides in adipose tissue) under conditions of nutrient abundance. FAO is composed of a cyclical series of reactions that result in the shortening of fatty acids (two carbons per cycle) and that generate in each round NADH, FADH2 and acetyl CoA, until the last cycle when two acetyl CoA molecules are originated from the catabolism of a four-carbon fatty acid (FIG. 1). NADH and FADH2 that are generated by FAO enter the electron transport chain (ETC) to produce ATP (FIG. 2). FAO is carried out in energy-demanding tissues (such as the heart and skeletal muscle) and in the liver as a central organ for nutrient supply and conversion.
We have summarized the metabolic switch as a programme in which the utilization of metabolic intermediates for anabolism prevails beyond ATP production. But there are situations in which cancer cells seem to require increased ATP production. This is exemplified by loss of attachment (LOA) to the extracellular matrix. Cells derived from solid tumours that undergo LOA display inhibition of glucose uptake and catabolism, which results in the loss of ATP, NADPH (as a result of decreased flux through the pentose phosphate pathway (PPP)) and increased production of reactive oxygen species (ROS) (FIG. 3). Schafer and co-workers11 showed that in these settings ROS inhibit FAO, and that antioxidants counteract ROS accumulation and can reactivate FAO, increase ATP levels and prevent LOA-induced anoikis, although the exact mechanism by which an increase in ATP rescues anoikis remains unclear.
Cancer metabolism can be perceived as a network of pathways with plasticity, feedback loops and crosstalk that ensure the fitness of tumour cells. Plasticity is key, and FAO might provide some of this plasticity by enabling the production of ATP and NADPH when required, eliminating potentially toxic lipids, inhibiting pro-apoptotic pathways and providing metabolic intermediates for cell growth. However, FAO cannot be perceived as a metabolic pathway that is active independently of the microenvironment of the cancer cell. Indeed, in ovarian cancers, which have a predilection to metastasize to the omentum (an adipocyte-rich tissue), the interaction with adipocytes is necessary for the transfer of lipids to the cancer cell, the activation of FAO and the establishment of metastasis38.
A big challenge is to unify the idea of FAO as an essential pathway in cancer cells with the fact that cancer cells also require active FAS in order to grow and divide. Dogma states that FAO and FAS are incompatible. In principle, ACC determines which pathway is active, on the basis of acetyl CoA and malonyl CoA levels. Therefore, as ACC is a ‘one-way street’, both metabolic activities cannot coexist. However, we might need to rethink such a rigid regulatory framework. The group of Nissim Hay32 showed that genetic manipulation of ACC1 or ACC2 in cancer cells yielded different outcomes in terms of FAS and FAO. In addition, FAO metabolism can contribute to the accumulation of acetyl CoA in the cytoplasm that is needed to initiate FAS, so that FAS and FAO can support each other23. On the basis of this idea, we can speculate that, rather than a total pool of acetyl CoA and malonyl CoA, there might be ACC1 and ACC2 localization-dependent compartmentalization39 of these metabolites that allows both metabolic pathways to be active simultaneously and independently from each other.
The data suggesting a greater requirement of FAO in undifferentiated cells also raise an interesting possibility. It is plausible that in quiescent and undifferentiated cells the competition between FAS and FAO may be less prominent (as these cells display a lower membrane synthesis rate), thus indicating that these cells might derive a full survival benefit from FAO activation and its biological output. In turn, their dependence on FAO could make them vulnerable, providing a unique therapeutic opportunity from the pharmacological manipulation of this metabolic pathway.
For all the reasons stated above, there is an exciting therapeutic potential for the pharmacological blockade of FAO in cancer. Two key enzymes in the FAO pathway are particularly interesting as potential targets for pharmacological intervention. CPT1 is considered the rate-limiting enzyme in FAO and can be pharmacologically targeted. Drugs that target 3-ketoacylthiolase (3-KAT), which catalyses the final step in FAO, are also available (TABLE 1).