Abstract
Nutritional imbalance underlies many disease processes but can be very beneficial in certain cases; for instance, the antiepileptic action of a high fat and low carbohydrate ketogenic diet. Besides this therapeutic feature it is not clear how this abundant fat supply may affect homeostasis, leading to side effects. A ketogenic diet is used as anti-seizure therapy i.a. in tuberous sclerosis patients, but its impact on concomitant tumor growth is not known. To examine this we have evaluated the growth of renal lesions in Eker rats (Tsc2+/−) subjected to a ketogenic diet for 4, 6 and 8 months. In spite of existing opinions about the anticancer actions of a ketogenic diet, we have shown that this anti-seizure therapy, especially in its long term usage, leads to excessive tumor growth. Prolonged feeding of a ketogenic diet promotes the growth of renal tumors by recruiting ERK1/2 and mTOR which are associated with the accumulation of oleic acid and the overproduction of growth hormone. Simultaneously, we observed that Nrf2, p53 and 8-oxoguanine glycosylase α dependent antitumor mechanisms were launched by the ketogenic diet. However, the pro-cancerous mechanisms finally took the ascendency by boosting tumor growth.
Highlights
Tuberous Sclerosis Complex (TSC) is a multi-system genetic disease caused by autosomal dominant mutations in the tumor suppressor genes encoding hamartin (TSC1) or tuberin (TSC2)
HFKD is a well appreciated anti-seizure therapy for TSC, but it has not been clearly established how it may affect the tumor growth related to this disorder
We have shown for the first time that HFKD promotes renal tumor growth in a rat model of TSC
Summary
Tuberous Sclerosis Complex (TSC) is a multi-system genetic disease caused by autosomal dominant mutations in the tumor suppressor genes encoding hamartin (TSC1) or tuberin (TSC2) Mutations in these genes result in the development of mostly non-neoplastic lesions which are found in many organs[1]. We believed that there was a need to evaluate how long-term HFKD might affect the development of TSC renal tumors. For this purpose, we used Eker rats with a spontaneous mutation in the Tsc[2] gene, which are an excellent animal model for studying TSC-related tumors[18]. Morphometric data was supported with a biochemical analysis to reveal the molecular mechanisms of HFKD action on renal tumorigenesis
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