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The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model.

Woolf EC, Curley KL, Liu Q, Turner GH, Charlton JA, Preul MC, Scheck AC - PLoS ONE (2015)

Bottom Line: Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B.Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin.Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.

View Article: PubMed Central - PubMed

Affiliation: Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute dba St. Joseph's Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America; School of Life Sciences, Arizona State University, Tempe, Arizona, 85281, United States of America.

ABSTRACT

Background: The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood.

Methods: To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma.

Results: Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.

Conclusions: The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas.

No MeSH data available.


Related in: MedlinePlus

Western blot analysis of ZO-1, occludin, aquaporin-1 and Aquaporin-4.(A) Western blots showing two representative samples per treatment group. (B,C) On day 21 post-implantation expression was quantified and represented as a fold change from SD (N = 6 for SD; N = 5 for KC; *p < 0.05; **p < 0.01).
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pone.0130357.g008: Western blot analysis of ZO-1, occludin, aquaporin-1 and Aquaporin-4.(A) Western blots showing two representative samples per treatment group. (B,C) On day 21 post-implantation expression was quantified and represented as a fold change from SD (N = 6 for SD; N = 5 for KC; *p < 0.05; **p < 0.01).

Mentions: Western blot analysis of tumor tissue was performed to analyze the expression of proteins involved with peritumoral edema and glioma progression including the tight junction proteins, ZO-1 and occludin, as well as the water channeling proteins, AQPN-1, AQPN-4. Tumors from animals fed KC had a significant increase in the expression of ZO-1 but no difference in occludin expression (Fig 8A and 8B). Animals maintained on KC also showed a reduction in expression of AQPN-4 expression but not AQPN-1 (Fig 8A and 8C).


The Ketogenic Diet Alters the Hypoxic Response and Affects Expression of Proteins Associated with Angiogenesis, Invasive Potential and Vascular Permeability in a Mouse Glioma Model.

Woolf EC, Curley KL, Liu Q, Turner GH, Charlton JA, Preul MC, Scheck AC - PLoS ONE (2015)

Western blot analysis of ZO-1, occludin, aquaporin-1 and Aquaporin-4.(A) Western blots showing two representative samples per treatment group. (B,C) On day 21 post-implantation expression was quantified and represented as a fold change from SD (N = 6 for SD; N = 5 for KC; *p < 0.05; **p < 0.01).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4470583&req=5

pone.0130357.g008: Western blot analysis of ZO-1, occludin, aquaporin-1 and Aquaporin-4.(A) Western blots showing two representative samples per treatment group. (B,C) On day 21 post-implantation expression was quantified and represented as a fold change from SD (N = 6 for SD; N = 5 for KC; *p < 0.05; **p < 0.01).
Mentions: Western blot analysis of tumor tissue was performed to analyze the expression of proteins involved with peritumoral edema and glioma progression including the tight junction proteins, ZO-1 and occludin, as well as the water channeling proteins, AQPN-1, AQPN-4. Tumors from animals fed KC had a significant increase in the expression of ZO-1 but no difference in occludin expression (Fig 8A and 8B). Animals maintained on KC also showed a reduction in expression of AQPN-4 expression but not AQPN-1 (Fig 8A and 8C).

Bottom Line: Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B.Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin.Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.

View Article: PubMed Central - PubMed

Affiliation: Neuro-Oncology Research, Barrow Brain Tumor Research Center, Barrow Neurological Institute dba St. Joseph's Hospital and Medical Center, Phoenix, Arizona, 85013, United States of America; School of Life Sciences, Arizona State University, Tempe, Arizona, 85281, United States of America.

ABSTRACT

Background: The successful treatment of malignant gliomas remains a challenge despite the current standard of care, which consists of surgery, radiation and temozolomide. Advances in the survival of brain cancer patients require the design of new therapeutic approaches that take advantage of common phenotypes such as the altered metabolism found in cancer cells. It has therefore been postulated that the high-fat, low-carbohydrate, adequate protein ketogenic diet (KD) may be useful in the treatment of brain tumors. We have demonstrated that the KD enhances survival and potentiates standard therapy in a mouse model of malignant glioma, yet the mechanisms are not fully understood.

Methods: To explore the effects of the KD on various aspects of tumor growth and progression, we used the immunocompetent, syngeneic GL261-Luc2 mouse model of malignant glioma.

Results: Tumors from animals maintained on KD showed reduced expression of the hypoxia marker carbonic anhydrase 9, hypoxia inducible factor 1-alpha, and decreased activation of nuclear factor kappa B. Additionally, tumors from animals maintained on KD had reduced tumor microvasculature and decreased expression of vascular endothelial growth factor receptor 2, matrix metalloproteinase-2 and vimentin. Peritumoral edema was significantly reduced in animals fed the KD and protein analyses showed altered expression of zona occludens-1 and aquaporin-4.

Conclusions: The KD directly or indirectly alters the expression of several proteins involved in malignant progression and may be a useful tool for the treatment of gliomas.

No MeSH data available.


Related in: MedlinePlus