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Liu J, Ramakrishnan SK, Khuder SS, et al. High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene. Mol Metab. 2015;4(3):186-98doi: 10.1016/j.molmet.2014.12.011.
Liu, J., Ramakrishnan, S. K., Khuder, S. S., Kaw, M. K., Muturi, H. T., Lester, S. G., Lee, S. J., Fedorova, L. V., Kim, A. J., Mohamed, I. E., Gatto-Weis, C., Eisenmann, K. M., Conran, P. B., & Najjar, S. M. (2015). High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene. Molecular metabolism, 4(3), 186-98. https://doi.org/10.1016/j.molmet.2014.12.011
Liu, Jehnan, et al. "High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene." Molecular metabolism vol. 4,3 (2015): 186-98. doi: https://doi.org/10.1016/j.molmet.2014.12.011
Liu J, Ramakrishnan SK, Khuder SS, Kaw MK, Muturi HT, Lester SG, Lee SJ, Fedorova LV, Kim AJ, Mohamed IE, Gatto-Weis C, Eisenmann KM, Conran PB, Najjar SM. High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene. Mol Metab. 2015 Jan 02;4(3):186-98. doi: 10.1016/j.molmet.2014.12.011. eCollection 2015 Mar. PMID: 25737954; PMCID: PMC4338312.
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Mol Metab. 2015 Jan 02;4(3):186-98. doi: 10.1016/j.molmet.2014.12.011. eCollection 2015 Mar.

High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene.

Molecular metabolism

Jehnan Liu, Sadeesh K Ramakrishnan, Saja S Khuder, Meenakshi K Kaw, Harrison T Muturi, Sumona Ghosh Lester, Sang Jun Lee, Larisa V Fedorova, Andrea J Kim, Iman E Mohamed, Cara Gatto-Weis, Kathryn M Eisenmann, Philip B Conran, Sonia M Najjar

Affiliations

  1. Center for Diabetes and Endocrine Research, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA ; Department of Physiology and Pharmacology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
  2. Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
  3. Department of Pathology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
  4. Department of Biochemistry and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.

PMID: 25737954 PMCID: PMC4338312 DOI: 10.1016/j.molmet.2014.12.011

Abstract

OBJECTIVE: Association between prostate cancer and obesity remains controversial. Allelic deletions of PTEN, a tumor suppressor gene, are common in prostate cancer in men. Monoallelic Pten deletion in mice causes low prostatic intraepithelial neoplasia (mPIN). This study tested the effect of a hypercaloric diet on prostate cancer in Pten (+/-) mice.

METHODS: 1-month old mice were fed a high-calorie diet deriving 45% calories from fat for 3 and 6 months before prostate was analyzed histologically and biochemically for mPIN progression. Because Pten (+/-) mice are protected against diet-induced insulin resistance, we tested the role of insulin on cell growth in RWPE-1 normal human prostatic epithelial cells with siRNA knockdown of PTEN.

RESULTS: In addition to activating PI3 kinase/Akt and Ras/MAPkinase pathways, high-calorie diet causes neoplastic progression, angiogenesis, inflammation and epithelial-mesenchymal transition. It also elevates the expression of fatty acid synthase (FAS), a lipogenic gene commonly elevated in progressive cancer. SiRNA-mediated downregulation of PTEN demonstrates increased cell growth and motility, and soft agar clonicity in addition to elevation in FAS in response to insulin in RWPE-1 normal human prostatic cells. Downregulating FAS in addition to PTEN, blunted the proliferative effect of insulin (and IL-6) in RWPE-1 cells.

CONCLUSION: High-calorie diet promotes prostate cancer progression in the genetically susceptible Pten haploinsufficient mouse while preserving insulin sensitivity. This appears to be partly due to increased inflammatory response to high-caloric intake in addition to increased ability of insulin to promote lipogenesis.

Keywords: Fatty acid synthase; Hyperinsulinemia; Neoplasia; PTEN tumor suppression; Prostate cancer

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