Modulation of prostate cancer cell proliferation and gene expression by dietary fatty acids and effects of adipocyte conditioned media

Open Access
Author:
Eser, Pinar Ozden
Graduate Program:
Molecular Medicine
Degree:
Master of Science
Document Type:
Master Thesis
Date of Defense:
April 02, 2012
Committee Members:
  • John Patrick Vanden Heuvel, Thesis Advisor
Keywords:
  • Prostate cancer
  • obesity
  • omega fatty acids
  • adipocytes
Abstract:
Fish oil contains the marine omega-3 polyunsaturated fatty acids (n-3 PUFA) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Consuming diets rich in these fatty acids has been associated with decreased incidence of prostate cancer, however much less is known about the non-marine n-3 PUFA alpha linolenic acid (ALA). To study which n-3 PUFA are more effective in prostate cancer prevention, and whether mechanisms of action are conserved between them, we tested DHA, EPA and ALA on the human prostate cancer cell line PC3. PC3 cells were treated with DHA, EPA, or ALA and changes in cell proliferation and gene expression examined. Different trends of inhibition of PC3 proliferation were observed for the three n-3 PUFA, with DHA exhibiting the most pronounced effects on PC3 cell proliferation and altered gene expression; ALA was the least efficacious of the three n-3 PUFA. All n-3 PUFA decreased fatty acid synthase (FASN) mRNA, and its regulator sterol response element binding protein 1c (SREBP-1c) mRNA to 50% of control levels. DHA, EPA and ALA decreased expression of macrophage chemotactic factor 1 (MCP1), an autocrine prostate cancer growth factor. Looking at genes involving inflammation, cell cycle and apoptosis, DHA regulated the greatest number of genes in all categories, followed by EPA and then ALA. In addition DHA and EPA increased gene expression of the pro-apoptotic protein activating transcription factor 3 (ATF3) mRNA by 11-fold and 3-fold, respectively while ALA had no effect. Moreover, DHA and EPA, but not ALA, significantly induced apoptosis. We conclude while some mechanisms of cancer cell inhibition are conserved among n-3 PUFA, the extent, magnitude, and duration of transcriptional changes vary for each individual fatty acid. Obesity in men, particularly an abundance of abdominal fat deposits, has been correlated with increased incidence and poor prognosis of prostate cancer. Fat may also affect the activity of prostate cancer cells that metastasize to bone, as the bones of older individuals are composed predominantly of fatty tissue. N-3 PUFA are effective agents in cancer prevention and therapy, although their precise mechanisms of action and the differences between them have not been fully characterized. In addition to omega-3 PUFA, other fatty acids, including certain omega-6 (n-6) PUFAs, and both 10-trans,12-cis (10e12z) and 9-cis,11-trans (9z11e) isomers of conjugated linoleic acid (CLA), also inhibit proliferation of PC3 prostate cancer cells. To mimic fat cells in the body, and determine whether the presence of these fat cells would affect the inhibitory actions of fatty acids, we used a two-step model of media preconditioning and treatment. Culture media containing inhibitory concentrations of fatty acids was first conditioned on 3T3-L1 adipocytes, and then administered to PC3 cells. Here, we show that 3T3-L1 adipocytes modulate the effects of fatty acid treatment, generally rendering the fatty acids less effective in proliferative inhibition of PC3 prostate cancer cells. The mechanism of inhibition of the PC3 cells’ response to fatty acids in the presence of fat cells may be significant to understanding the correlation between obesity and resistance to prostate cancer therapy.