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


CONCLUSIONS
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.
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.
Jehnan
J
Liu
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.
Sadeesh K
SK
Ramakrishnan
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.
Saja S
SS
Khuder
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.
Meenakshi K
MK
Kaw
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.
Harrison T
HT
Muturi
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.
Sumona Ghosh
SG
Lester
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.
Sang Jun
SJ
Lee
Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
Larisa V
LV
Fedorova
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.
Andrea J
AJ
Kim
Department of Medicine, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
Iman E
IE
Mohamed
Department of Pathology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
Cara
C
Gatto-Weis
Department of Biochemistry and Cancer Biology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
Kathryn M
KM
Eisenmann
Department of Pathology, The University of Toledo College of Medicine and Life Sciences, Toledo, OH, 43614, USA.
Philip B
PB
Conran
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.
Sonia M
SM
Najjar
Fatty acid synthase; Hyperinsulinemia; Neoplasia; PTEN tumor suppression; Prostate cancer