A low carbohydrate, high protein diet suppresses intratumoral androgen synthesis and slows castration-resistant prostate tumor growth in mice

J Steroid Biochem Mol Biol. 2015 Jun;150:35-45. doi: 10.1016/j.jsbmb.2015.03.006. Epub 2015 Mar 19.

Abstract

Dietary factors continue to preside as dominant influences in prostate cancer prevalence and progression-free survival following primary treatment. We investigated the influence of a low carbohydrate diet, compared to a typical Western diet, on prostate cancer (PCa) tumor growth in vivo. LNCaP xenograft tumor growth was studied in both intact and castrated mice, representing a more advanced castration resistant PCa (CRPC). No differences in LNCaP tumor progression (total tumor volume) with diet was observed for intact mice (P = 0.471) however, castrated mice on the Low Carb diet saw a statistically significant reduction in tumor growth rate compared with Western diet fed mice (P = 0.017). No correlation with serum PSA was observed. Steroid profiles, alongside serum cholesterol and cholesteryl ester levels, were significantly altered by both diet and castration. Specifically, DHT concentration with the Low Carb diet was 58% that of the CRPC-bearing mice on the Western diet. Enzymes in the steroidogenesis pathway were directly impacted and tumors isolated from intact mice on the Low Carb diet had higher AKR1C3 protein levels and lower HSD17B2 protein levels than intact mice on the Western diet (ARK1C3: P = 0.074; HSD17B2: P = 0.091, with α = 0.1). In contrast, CRPC tumors from mice on Low Carb diets had higher concentrations of both HSD17B2 (P = 0.016) and SRD5A1 (P = 0.058 with α = 0.1) enzymes. There was no correlation between tumor growth in castrated mice for Low Carb diet versus Western diet and (a) serum insulin (b) GH serum levels (c) insulin receptor (IR) or (d) IGF-1R in tumor tissue. Intact mice fed Western diet had higher serum insulin which was associated with significantly higher blood glucose and tumor tissue IR. We conclude that both diet and castration have a significant impact on the endocrinology of mice bearing LNCaP xenograft tumors. The observed effects of diet on cholesterol and steroid regulation impact tumor tissue DHT specifically and are likely to be mechanistic drivers behind the observed tumor growth suppression.

Keywords: CRPC; Intratumoral androgens; Low carbohydrate high protein diet; Prostate cancer; Steroidogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3-Hydroxysteroid Dehydrogenases / genetics
  • 3-Hydroxysteroid Dehydrogenases / metabolism
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / genetics
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase / metabolism
  • Adenocarcinoma / diet therapy*
  • Adenocarcinoma / genetics
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / pathology
  • Aldo-Keto Reductase Family 1 Member C3
  • Androgens / biosynthesis*
  • Animals
  • Blood Glucose / metabolism
  • Castration
  • Cholesterol / blood
  • Cholesterol Esters / blood
  • Diet, Carbohydrate-Restricted*
  • Diet, Western
  • Dietary Proteins / administration & dosage*
  • Estradiol Dehydrogenases / genetics
  • Estradiol Dehydrogenases / metabolism
  • Gene Expression Regulation
  • Growth Hormone / blood
  • Humans
  • Hydroxyprostaglandin Dehydrogenases / genetics
  • Hydroxyprostaglandin Dehydrogenases / metabolism
  • Insulin / blood
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Neoplasm Transplantation
  • Prostate / drug effects
  • Prostate / metabolism
  • Prostate / pathology
  • Prostate-Specific Antigen / blood
  • Prostatic Neoplasms, Castration-Resistant / diet therapy*
  • Prostatic Neoplasms, Castration-Resistant / genetics
  • Prostatic Neoplasms, Castration-Resistant / metabolism
  • Prostatic Neoplasms, Castration-Resistant / pathology
  • Receptor, IGF Type 1 / genetics
  • Receptor, IGF Type 1 / metabolism
  • Receptor, Insulin / genetics
  • Receptor, Insulin / metabolism
  • Transplantation, Heterologous
  • Tumor Burden / drug effects

Substances

  • Androgens
  • Blood Glucose
  • Cholesterol Esters
  • Dietary Proteins
  • Insulin
  • Membrane Proteins
  • Growth Hormone
  • Cholesterol
  • 3-Hydroxysteroid Dehydrogenases
  • Hydroxyprostaglandin Dehydrogenases
  • AKR1C3 protein, human
  • Aldo-Keto Reductase Family 1 Member C3
  • Estradiol Dehydrogenases
  • HSD17B2 protein, human
  • 3-Oxo-5-alpha-Steroid 4-Dehydrogenase
  • SRD5A1 protein, human
  • Receptor, IGF Type 1
  • Receptor, Insulin
  • Prostate-Specific Antigen