BERKELEY, CA (UroToday.com) - In our recent article in the journal Oncogene, we proposed a new therapeutic approach targeting metabolic pathways in prostate cancer cells.
It is today known that one of the hallmarks of cancer cells is a specific change in metabolism, comprising changes in glucose utilization and the use of lipid synthesis pathways. Our rationale-based approach was initiated by the observation that prostate cancer cells show an increase in de novo synthesis of fatty acids. We also knew that drug inhibition of fatty acid synthase (FASN), which is a major enzyme involved in lipogenesis, results in cancer cell death. Most of the previous studies using this drug supported the hypothesis that FASN inhibition results in the accumulation of malonyl CoA, which has deleterious effects on the cell, including inhibition of cell growth and apoptosis. Taking these observations into account, we explored the possibility to induce, even more, the accumulation of malonyl CoA in cancer cells.
With this aim, we analyzed in detail the specific metabolic pathway leading to malonyl CoA formation and utilization. Anaerobic glycolysis, which is typically used by cancer cells, ultimately results in both lactic acid and acetyl CoA formation, the latest being a precursor of fatty acid synthesis. Acetyl CoA carboxylase (ACC) is the enzyme that catalyzes the conversion of acetyl CoA into malonyl CoA, which will be further converted into palmitate, by FASN. We thought then, that if we could accelerate the conversion of acetyl CoA into malonyl CoA while we block the conversion of malonyl CoA into palmitate, we would reach our aim to increase malonyl CoA formation, and therefore force cancer cells to die because of the accumulation of this toxic product. We therefore blocked FASN activity using chemical inhibitors such as the compound C75. Next, the question was how to induce the activity of ACC1 to accelerate malonyl CoA production. Since chemical activators of this enzyme were not available, we decided to use inhibitors of proteins known to negatively regulate ACC1 activity. One of the first ACC1 modulators identified is the AMP-regulated protein kinase, AMPK. Indeed, inhibition of AMPK resulted in the activation of ACC1 with a higher rate of malonyl CoA formation in the prostate cancer cell lines that we used. Concomitant with the inhibition of malonyl CoA utilization by FASN, this treatment resulted in the arrest of cancer cells' growth both in cellular and in xenografted mice models of prostate cancer.
These results emphasize the importance of manipulating metabolic pathways in order to interfere with the growth of a cell, a cancer cell in our study. We like to call this strategy metabolic bioengineering, and we think that there are almost unlimited opportunities to design new strategies for cancer treatment based on metabolic features. Our results also underscore the need to better understand which are the metabolic pathways that cancer cells specifically undertake in order to growth and spread. This therapeutic strategy can be compared to car traffic regulation in a big city as an illustration. Using mandatory road signs (similar to providing a specific substrate or activating a particular pathway in the cell) or fixing forbidden access panels (that resembles inhibition of a specific enzymatic reaction) we could eventually force a car driver (called the cell) to take a particular road directly to the cliff (apoptosis). New strategies targeting metabolism of cancer cells warrant further testing.
Written by:
Lluis Fajas as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Director, Department of Physiology, Université de Lausanne, Rue du Bugnon 7, CH1005 Lausanne, Switzerland
Metabolic intervention on lipid synthesis converging pathways abrogates prostate cancer growth - Abstract
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