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The Ketogenic Diet Does Not Affect Growth of Hedgehog Pathway Medulloblastoma in Mice.

Dang MT, Wehrli S, Dang CV, Curran T - PLoS ONE (2015)

Bottom Line: The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention.Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed.These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention. In particular, brain tumors often display heightened glycolysis, even in the presence of oxygen. A subset of medulloblastoma, the most prevalent malignant brain tumor in children, arises as a consequence of activating mutations in the Hedgehog (HH) pathway, which has been shown to promote aerobic glycolysis. Therefore, we hypothesized that a low carbohydrate, high fat ketogenic diet would suppress tumor growth in a genetically engineered mouse model of medulloblastoma. However, we found that the ketogenic diet did not slow the growth of spontaneous tumors or allograft flank tumors, and it did not exhibit synergy with a small molecule inhibitor of Smoothened. Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed. These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

No MeSH data available.


Related in: MedlinePlus

The ketogenic diet causes a significant decrease in insulin, but does not affect the PI3K pathway.(A) Insulin levels were significantly reduced by 2 days after initiation of the diet. Average serum concentration was 1.64 ng/ml on the standard diet in comparison to 0.45 ng/ml on the ketogenic diet (p = 0.003). (B) Phosphorylated AKT was present in tumor tissues and the level of phosphorylation was not significantly different between the two groups treated with different diets (p = 0.89 standardized to GAPDH, p = 0.64 standardized to AKT). (C) Foxo3a was localized in the cytoplasm independent of the diet. S = standard diet, K = ketogenic diet.
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pone.0133633.g003: The ketogenic diet causes a significant decrease in insulin, but does not affect the PI3K pathway.(A) Insulin levels were significantly reduced by 2 days after initiation of the diet. Average serum concentration was 1.64 ng/ml on the standard diet in comparison to 0.45 ng/ml on the ketogenic diet (p = 0.003). (B) Phosphorylated AKT was present in tumor tissues and the level of phosphorylation was not significantly different between the two groups treated with different diets (p = 0.89 standardized to GAPDH, p = 0.64 standardized to AKT). (C) Foxo3a was localized in the cytoplasm independent of the diet. S = standard diet, K = ketogenic diet.

Mentions: Insulin levels were significantly reduced 2 days after initiation of the ketogenic diet. The average serum concentration was 1.64 ng/ml on the standard diet in comparison with 0.45 ng/ml on the ketogenic diet (n = 5,9; p = 0.003, Fig 3A). Insulin is a known regulator of PI3K pathway. Insulin and insulin-like growth factors activate PI3K which phosphorylates AKT [27]. Among the multiple functions of AKT is phosphorylation of forkhead box O (FoxO) transcription factor family proteins in the nucleus. Phosphorylation displaces the FoxO transcription factors from target genes that promote apoptosis or cell-cycle arrest and trigger their relocalization to the cytoplasm [28]. We measured the level of phosphorylated AKT and stained for localization of Foxo3a in mice with ketogenic diet-induced insulin reduction. Phosphorylated AKT was present at low levels in HH-MB tissue and was not significantly different between the two groups treated with different diets (Fig 3B, p = 0.89 standardized to GAPDH, p = 0.64 standardized to AKT). Foxo3a was mainly localized to the cytoplasm and also was unchanged in both groups (Fig 3C).


The Ketogenic Diet Does Not Affect Growth of Hedgehog Pathway Medulloblastoma in Mice.

Dang MT, Wehrli S, Dang CV, Curran T - PLoS ONE (2015)

The ketogenic diet causes a significant decrease in insulin, but does not affect the PI3K pathway.(A) Insulin levels were significantly reduced by 2 days after initiation of the diet. Average serum concentration was 1.64 ng/ml on the standard diet in comparison to 0.45 ng/ml on the ketogenic diet (p = 0.003). (B) Phosphorylated AKT was present in tumor tissues and the level of phosphorylation was not significantly different between the two groups treated with different diets (p = 0.89 standardized to GAPDH, p = 0.64 standardized to AKT). (C) Foxo3a was localized in the cytoplasm independent of the diet. S = standard diet, K = ketogenic diet.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507880&req=5

pone.0133633.g003: The ketogenic diet causes a significant decrease in insulin, but does not affect the PI3K pathway.(A) Insulin levels were significantly reduced by 2 days after initiation of the diet. Average serum concentration was 1.64 ng/ml on the standard diet in comparison to 0.45 ng/ml on the ketogenic diet (p = 0.003). (B) Phosphorylated AKT was present in tumor tissues and the level of phosphorylation was not significantly different between the two groups treated with different diets (p = 0.89 standardized to GAPDH, p = 0.64 standardized to AKT). (C) Foxo3a was localized in the cytoplasm independent of the diet. S = standard diet, K = ketogenic diet.
Mentions: Insulin levels were significantly reduced 2 days after initiation of the ketogenic diet. The average serum concentration was 1.64 ng/ml on the standard diet in comparison with 0.45 ng/ml on the ketogenic diet (n = 5,9; p = 0.003, Fig 3A). Insulin is a known regulator of PI3K pathway. Insulin and insulin-like growth factors activate PI3K which phosphorylates AKT [27]. Among the multiple functions of AKT is phosphorylation of forkhead box O (FoxO) transcription factor family proteins in the nucleus. Phosphorylation displaces the FoxO transcription factors from target genes that promote apoptosis or cell-cycle arrest and trigger their relocalization to the cytoplasm [28]. We measured the level of phosphorylated AKT and stained for localization of Foxo3a in mice with ketogenic diet-induced insulin reduction. Phosphorylated AKT was present at low levels in HH-MB tissue and was not significantly different between the two groups treated with different diets (Fig 3B, p = 0.89 standardized to GAPDH, p = 0.64 standardized to AKT). Foxo3a was mainly localized to the cytoplasm and also was unchanged in both groups (Fig 3C).

Bottom Line: The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention.Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed.These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.

ABSTRACT
The altered metabolism of cancer cells has long been viewed as a potential target for therapeutic intervention. In particular, brain tumors often display heightened glycolysis, even in the presence of oxygen. A subset of medulloblastoma, the most prevalent malignant brain tumor in children, arises as a consequence of activating mutations in the Hedgehog (HH) pathway, which has been shown to promote aerobic glycolysis. Therefore, we hypothesized that a low carbohydrate, high fat ketogenic diet would suppress tumor growth in a genetically engineered mouse model of medulloblastoma. However, we found that the ketogenic diet did not slow the growth of spontaneous tumors or allograft flank tumors, and it did not exhibit synergy with a small molecule inhibitor of Smoothened. Serum insulin was significantly reduced in mice fed the ketogenic diet, but no alteration in PI3 kinase activity was observed. These findings indicate that while the ketogenic diet may be effective in inhibiting growth of other tumor types, it does not slow the growth of HH-medulloblastoma in mice.

No MeSH data available.


Related in: MedlinePlus