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Lipid metabolism: New fuels for cancer, new targets for therapy

Colorectal cancer (CRC) is one of the most deadly and prevalent cancers in the developed world 1. Among the risk factors for developing the disease, factors related to lifestyle such as lack of physical activity, smoking and westernized diets -high in red or processed meats and poor in vegetables- are included 2. In fact, according to WHO, one-third of all cancers are preventable with lifestyle factors as diet.

There is increasing evidence of the decisive contribution of these factors determining the amount and the nature of the energy supply for cancer cells and metabolic reprogramming is now one of the emerging hallmarks of cancer. In addition to well-known carbohydrate metabolism alterations, such as Warburg effect by which cancer cells preferentially drive glucose metabolism to lactate production under aerobic conditions3, other metabolic pathways alterations demand further attention. Lipid metabolism represents a relevant source of energy and structural and biosynthetic resources and has been demonstrated to be key to invasion and cancer pathogenesis 4,5.

In the Molecular Oncology and Nutrition Cancer Genetics group, we have recently discovered a new connection between lipid metabolism and CRC that helps to understand the role of diet and metabolism in these tumors. We have described a link between high levels of lipid metabolism key enzymes in patients with CRC and increased aggressiveness of the disease 6. These enzymes act as a collaborative network, the acyl-CoA synthetase/ stearoyl-CoA desaturase (ACSL/SCD) network, composed by the members of the fatty acid activating enzymes ACSL1 and ACSL4 and the SCD fatty acid desaturase. This metabolic network activates cellular pathways such as Erk, β-Cat and Akt that confer tumor cells increased ability to migrate and invade other tissues, key to the development of metastasis, through a process known as epithelial-mesenchymal transition (EMT) 7. This effect relies on an energetic advantage that can be reverted through reactivation of the master regulator of cell energy balance, the AMPK kinase.

Therefore, this ACSL/SCD metabolic switch is an example of how different types of metabolic reprogramming can be used by tumors to increase their malignity depending on the needs and the environment (Figure 1).  Very importantly, the treatment with specific inhibitors for these enzymes is able to cause the cell death of CRC cells without affecting normal cells. Therefore, the use of these drugs in clinical practice as a new way of addressing tumor metabolism might represent a promising therapeutic strategy for the treatment of CRC. 

Figure 1: The combined action of ACSL1, ACSL4 and SCD (ACSL/SCD network) confers an energetic advantage to tumor cells that stimulates several EMT-promoting and survival pathways. Lipid metabolism switches Warburg-like tumor metabolism into EMT-like tumor metabolism leading to a gain of migratory and invasive capabilities. This process can be reversed upon re-activation of AMPK signaling.

References

1.             Siegel, R., Naishadham, D. & Jemal, A. Cancer statistics, 2012. CA. Cancer J. Clin. 62, 10–29 (2012).

2.             Esposito, K. et al. Colorectal cancer association with metabolic syndrome and its components: a systematic review with meta-analysis. Endocrine 44, 634–647 (2013).

3.             Warburg, O. On the origin of cancer cells. Science 123, 309–314 (1956).

4.             Carracedo, A., Cantley, L. C. & Pandolfi, P. P. Cancer metabolism: fatty acid oxidation in the limelight. Nat. Rev. Cancer 13, 227–232 (2013).

5.             Nomura, D. K. et al. Monoacylglycerol lipase regulates a fatty acid network that promotes cancer pathogenesis. Cell 140, 49–61 (2010).

6.             Sánchez-Martínez, R. et al. A link between lipid metabolism and epithelial-mesenchymal transition provides a target for colon cancer therapy. Oncotarget 6, 38719–38736 (2015).

7.             Nieto, M. A. & Cano, A. The epithelial-mesenchymal transition under control: global programs to regulate epithelial plasticity. Semin. Cancer Biol. 22, 361–368 (2012).

 

 

 

Event Date: 
Monday, June 27, 2016