Prostate cancer (PCa) is among the leading causes of male cancer-related morbidity and death, second only to lung cancer, representing approximately 10% of all cancer deaths among men in the United States. Prospective cohort studies have shown a statistically significant positive association between obesity and the risk of death from PCa. Consistent with these observations, it has been noted that caloric restriction acts to prevent cancer progression. It was initially thought that the effects of caloric restriction on tumor progression were a secondary response to decreased cell growth;however, it is increasingly being recognized that this process actually impinges on key intracellular signaling pathways, particularly the insulin-IGFI and nutrient- mediated PI3K/ mTORCI signaling pathway, which is opposed by a large number of tumor suppressors including PTEN, TSC1/2, NF1, LKB1, 4E-BP1, PDCD4, and PML. Clearly, further resolution of the molecular mechanisms linking obesity to PCa cannot rely on epidemiological studies alone, but will require the use of mouse models that integrate knowledge obtained from human cancer studies. The project proposed here will examine the role of diet in PCa at a cellular and molecular level by using genetically engineered mice that harbor a specific lesion in the Pten gene. This model will be used in the following experiments: (i) determine the impact of a high-fat diet, ketogenic diet, and dietary constituents or caloric intake in PCa development;(ii) test the hypothesis that hypercholesterolemia promotes PCa progression and that it is related to dysfunctional feedback regulation of the low-density lipoprotein (LDL) receptor, and assess the influence of endogenous production of cholesterol and isoprenoids on cancer progression;(iii) test the effect of excess dietary branched-chain amino acids on PCa progression and the role of mTORCI signaling in this response, and determine whether the effect of caloric restriction on PCa is recapitulated by rapamycin and metformin;(iv) ascertain the mechanism of AMPK pathway regulation by PML in PCa and the therapeutic implications of the PML-AMPK pathway in PCa by employing established PCa chemotherapy and chemoprevention protocols. This timely study in cancer biology will be directed by present members of the NCI-MMHCC and the NIDDK-MMPC.
Over the course of a lifetime, one in six men in the United States will be diagnosed with prostate cancer. Multiple factors contribute to the high incidence and prevalence of prostate cancer. Among these, obesity is an increasingly important risk factor. This project will examine the role of diet in the progression of prostate cancer and as an avenue for designing new therapeutic approaches based on existing mouse models.
|Ressler, Ilana B; Grayson, Bernadette E; Ulrich-Lai, Yvonne M et al. (2015) Diet-induced obesity exacerbates metabolic and behavioral effects of polycystic ovary syndrome in a rodent model. Am J Physiol Endocrinol Metab 308:E1076-84|
|Stemmer, Kerstin; Zani, Fabio; Habegger, Kirk M et al. (2015) FGF21 is not required for glucose homeostasis, ketosis or tumour suppression associated with ketogenic diets in mice. Diabetologia 58:2414-23|
|Ressler, Ilana B; Grayson, Bernadette E; Seeley, Randy J (2014) Metabolic, behavioral, and reproductive effects of vertical sleeve gastrectomy in an obese rat model of polycystic ovary syndrome. Obes Surg 24:866-76|
|Grayson, Bernadette E; Hakala-Finch, Andrew P; Kekulawala, Melani et al. (2014) Weight loss by calorie restriction versus bariatric surgery differentially regulates the hypothalamo-pituitary-adrenocortical axis in male rats. Stress 17:484-93|
|Grayson, B E; Fitzgerald, M F; Hakala-Finch, A P et al. (2014) Improvements in hippocampal-dependent memory and microglial infiltration with calorie restriction and gastric bypass surgery, but not with vertical sleeve gastrectomy. Int J Obes (Lond) 38:349-56|
|Grayson, Bernadette E; Schneider, Katarina M; Woods, Stephen C et al. (2013) Improved rodent maternal metabolism but reduced intrauterine growth after vertical sleeve gastrectomy. Sci Transl Med 5:199ra112|
|Grayson, Bernadette E; Seeley, Randy J; Sandoval, Darleen A (2013) Wired on sugar: the role of the CNS in the regulation of glucose homeostasis. Nat Rev Neurosci 14:24-37|
|Kim, D-H; Gutierrez-Aguilar, R; Kim, H-J et al. (2013) Increased adipose tissue hypoxia and capacity for angiogenesis and inflammation in young diet-sensitive C57 mice compared with diet-resistant FVB mice. Int J Obes (Lond) 37:853-60|
|Grayson, B E; Seeley, R J (2012) Deconstructing obesity: the face of fatness before and after the discovery of leptin. Diabetologia 55:3-6|
|Thomas, Hala Elnakat; Mercer, Carol A; Carnevalli, Larissa S et al. (2012) mTOR inhibitors synergize on regression, reversal of gene expression, and autophagy in hepatocellular carcinoma. Sci Transl Med 4:139ra84|
Showing the most recent 10 out of 13 publications