Myristoylation of Src Kinase Mediates Src-Induced and High-Fat Diet Accelerated Prostate Tumor Progression in Mice: Beyond the Abstract

The research community has made significant efforts in determining the relationship between increased cancer risk and diet. The overall scientific consensus is that obesity increases the risk of prostate cancer progression and leads to poorer therapeutic outcomes. Because of difficulties in documenting people's diet, large-scale epidemiological studies have not been able to resolve a clear correlation between a high-fat diet and cancer. The purpose of our study was to decipher experimentally whether a high-fat diet elevates the activity of Src kinase, a commonly over-expressed and/or activated oncogene in prostate cancer, to discover the biological mechanisms of dietary effect on cancer progression.

Our study demonstrates that dietary saturated fatty acids synergize with Src kinase, which results in a poor outcome in prostate cancer progression. Saturated fatty acids such as myristic acid (MA, 14-carbon saturated fatty acid) significantly enhance the activity of the oncoprotein Src kinase and promote its mediated oncogenic signaling. Elevated levels of MA in the form of myristoyl-CoA have been found in cancerous tumors in experiments with a high-fat diet. This evidence suggests that cancer patients might face health threats from daily dietary MA, since some elements common in high-fat diets, such as butter and coconut oil, often contain high levels of MA. Butter and coconut oil contain 8.3g/100g and 17g/100g of MA, respectively. These high MA levels could pose a significant problem for Americans because they are some of the top consumers of coconut oil in the world. According to the US Department of Agriculture, Americans also reached a 40-year record high in butter consumption in 2014. Americans consume 6-fold higher amounts of MA and 4-fold higher amounts of coconut oil in comparison with the Japanese, a nation with significantly lower prostate cancer incidence than the US.

Mechanistically, dietary MA could serve to modify Src kinase co/post-translationally. Src kinase is known to be an oncogenic driver in advanced stages of prostate cancer. Over-expression and/or activation of Src kinase are associated with the proliferation and invasion of cancer cells. The bioconversion of dietary MA to myristoyl-CoA potentially provides a substrate to biosynthesize the myristoylated Src kinase. As a result, the process elevates expression levels of Src kinase in the cellular membrane, subsequently enhancing its oncogenic potential in prostate tumor progression.

Dasatinib (Sprycel) from Bristol-Myers Squibb has been approved by the FDA for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia. This drug has a significantly inhibitory effect on Src kinase activity and Src-mediated tumorigenesis. Sprycel has been used in a clinic trial as a treatment for prostate cancer. Our experiments indicate that the therapeutic effects were significantly compromised by a high-fat diet. This effect might be through the participation of MA in the Src protein folding process, which favors the activated state of Src kinase, or simply through the elevation of Src activity. Therefore, the clinic trial for dasatinib might need to consider the dietary factor effect in the experimental design.

Ultimately, "you are what you eat." Dietary fat plays an important role in the acceleration of cancer progression. Dietary saturated fatty acids aggravate Src-mediated prostate cancer.

Written by: Houjian Cai 

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