Marine and plant derived n minus 3 fatty acids differentially regulate prostate cancer cell proliferation
Marine and plant derived n minus 3 fatty acids differentially regulate prostate cancer cell proliferation
Year: 2013
Authors: Eser, P.O. Vandenheuvel, J.P. Araujo, J. Thompson, J.T.
Publication Name: Mol Clin Oncol.
Publication Details: Volume 1; Number 3; pages 444-452.
Abstract:
Fish oil contains the marine n3 polyunsaturated fatty acids (n3 PUFAs) docosahexaenoic (DHA) and eicosapentaenoic acid (EPA). The consumption of diets rich in these fatty acids is associated with a decreased incidence of prostate cancer. However, there is limited knowledge regarding the non marine n minus 3 PUFA alpha linolenic acid (ALA). To study which n3 PUFAs are more effective in prostate cancer prevention, and whether the mechanisms of action are conserved between them, we investigated the effect of DHA, EPA and ALA on the human prostate cancer cell lines PC3 and LNCaP. Different trends of inhibition of PC3 cell proliferation were observed for the three n3 PUFA, with DHA having the most pronounced effects on cell proliferation, while ALA had the minimum effects of the three n3 PUFAs. All the n3 PUFAs decreased fatty acid synthase (FASN) mRNA. Concerning genes involved in inflammation, cell cycle and apoptosis, DHA regulated the most genes in all categories, followed by EPA and then ALA. In addition, DHA and EPA increased the gene expression of the pro apoptotic protein activating transcription factor 3 mRNA. Moreover, these two fatty acids significantly induced apoptosis. In conclusion, while some mechanisms of cancer cell inhibition are conserved among n3 PUFA, the extent, magnitude, and duration of transcriptional changes vary for each individual fatty acid. (Authors Abstract)
Prostate cancer is one of the most commonly diagnosed types of cancer in males as well as the second leading cause of cancer death in males in the United States. Metastatic prostate cancer is incurable, and the primary treatment consists of androgen deprivation, which leads to apoptosis of cancer cells and regression of tumors. Prostate cancer has long been linked to obesity and nutrition in incidence and mortality, although the role of dietary fatty acids in the etiology or prevention of this disease has not been fully elucidated yet. Fatty acids are the primary energy source for prostate cancer cells and androgens upregulate fatty acid synthase (FASN), the enzyme responsible for the de novo synthesis of fatty acids. FASN is increased in prostate adenocarcinoma as compared to normal prostatic tissue and is a marker of prostate cancer recurrence, poor prognosis and higher Gleason grade. Sterol response element binding protein1c (SREBP1c) is a positive regulator of FASN expression through binding elements in the FASN promoter. Diets rich in n3 polyunsaturated fatty acids suppress SREBP 1 mRNA and the active nuclear form of the SREBP1 protein. Androgen ablation and androgen receptor (AR) antagonism therapy in patients with prostate cancer initially induces cell cycle arrest and apoptosis. However, cancer cells eventually lose dependence on androgens, leading to progression of the androgen independent tumors. Cytokines and chemokines, produced by activated resident immune cells, are the most important components regulating the tumor growth microenvironment. Both androgen dependent and independent prostate cancer cells produce high levels of the macrophage chemotactic protein 1 (MCP 1) compared to normal prostate epithelial cells. MCP 1 acts as an autocrine growth and prometastatic factor in prostate cancer. Notably, proinflammatory cytokines such as interleukin (IL) 1, IL 6 and tumor necrosis factor (TNF) are able to affect cancer risk. An increase in dietary n 3 fatty acids has been linked to good prostate health and prevention of prostate cancer progression to androgen independence. To better understand the effects of individual fatty acids and to gain insight into potential mechanisms that may benefit prostate cancer patients, the prostate cancer cell lines PC 3 and LNCaP, which represent androgen independent and dependent disease, respectively, were used in this study to determine whether PUFAs have a suppressive effect on cell proliferation. Although all the fatty acids decreased the cell viability of androgen dependent and independent cell lines, they were demonstrated to have different rates of activity. The treatment of androgenindependent (PC 3) and dependent (LNCaP) prostate cancer cell lines with individual n 3 fatty acids at 100 micro M inhibited cell growth in a time dependent manner. ALA was examined at the same concentration even though most studies indicate that basal levels are lower compared to those for DHA and EPA with ranges from 7 to 25 micro M and supplementation levels only reaching 35 micro M. All the n 3 fatty acids effectively inhibited the proliferation of PC 3 and LNCaP prostate cancer cells. The androgen dependent LNCaP cell line demonstrated a delay in response that may be attributed to the slower cell division observed in this cell line as compared to PC 3 cells. DHA was the most efficient and potent inhibitor of PC 3 proliferation, followed by EPA and then ALA. The observation that ALA was the least toxic of the fatty acids examined indicates that, although the 100 micro M concentration has not been reported in vivo, overt toxicity with this molecule in the cell model used in this study is unlikely. All the n 3 PUFAs examined modulated fatty acid synthesis by decreasing the accumulation of SREBP 1c mRNA. None of the n 3 fatty acids used in this study altered the transcription of LDLR or SREBP 2, a potent regulator of the LDLR promoter, indicating that this pathway was not involved in the observed inhibition. While all the n 3 fatty acids examined resulted in equal inhibition of SREBP 1c and FASN (50 per cent reduction), they exhibited different efficiencies in the inhibition of proliferation. This suggested that alternative apoptotic or anti proliferative mechanisms needed to be invoked to cause the more substantial inhibitory trends observed following DHA and EPA treatment of PC 3 and LNCaP cells.
Prostate cancer is one of the most commonly diagnosed types of cancer in males as well as the second leading cause of cancer death in males in the United States. Metastatic prostate cancer is incurable, and the primary treatment consists of androgen deprivation, which leads to apoptosis of cancer cells and regression of tumors. Prostate cancer has long been linked to obesity and nutrition in incidence and mortality, although the role of dietary fatty acids in the etiology or prevention of this disease has not been fully elucidated yet. Fatty acids are the primary energy source for prostate cancer cells and androgens upregulate fatty acid synthase (FASN), the enzyme responsible for the de novo synthesis of fatty acids. FASN is increased in prostate adenocarcinoma as compared to normal prostatic tissue and is a marker of prostate cancer recurrence, poor prognosis and higher Gleason grade. Sterol response element binding protein1c (SREBP1c) is a positive regulator of FASN expression through binding elements in the FASN promoter. Diets rich in n3 polyunsaturated fatty acids suppress SREBP 1 mRNA and the active nuclear form of the SREBP1 protein. Androgen ablation and androgen receptor (AR) antagonism therapy in patients with prostate cancer initially induces cell cycle arrest and apoptosis. However, cancer cells eventually lose dependence on androgens, leading to progression of the androgen independent tumors. Cytokines and chemokines, produced by activated resident immune cells, are the most important components regulating the tumor growth microenvironment. Both androgen dependent and independent prostate cancer cells produce high levels of the macrophage chemotactic protein 1 (MCP 1) compared to normal prostate epithelial cells. MCP 1 acts as an autocrine growth and prometastatic factor in prostate cancer. Notably, proinflammatory cytokines such as interleukin (IL) 1, IL 6 and tumor necrosis factor (TNF) are able to affect cancer risk. An increase in dietary n 3 fatty acids has been linked to good prostate health and prevention of prostate cancer progression to androgen independence. To better understand the effects of individual fatty acids and to gain insight into potential mechanisms that may benefit prostate cancer patients, the prostate cancer cell lines PC 3 and LNCaP, which represent androgen independent and dependent disease, respectively, were used in this study to determine whether PUFAs have a suppressive effect on cell proliferation. Although all the fatty acids decreased the cell viability of androgen dependent and independent cell lines, they were demonstrated to have different rates of activity. The treatment of androgenindependent (PC 3) and dependent (LNCaP) prostate cancer cell lines with individual n 3 fatty acids at 100 micro M inhibited cell growth in a time dependent manner. ALA was examined at the same concentration even though most studies indicate that basal levels are lower compared to those for DHA and EPA with ranges from 7 to 25 micro M and supplementation levels only reaching 35 micro M. All the n 3 fatty acids effectively inhibited the proliferation of PC 3 and LNCaP prostate cancer cells. The androgen dependent LNCaP cell line demonstrated a delay in response that may be attributed to the slower cell division observed in this cell line as compared to PC 3 cells. DHA was the most efficient and potent inhibitor of PC 3 proliferation, followed by EPA and then ALA. The observation that ALA was the least toxic of the fatty acids examined indicates that, although the 100 micro M concentration has not been reported in vivo, overt toxicity with this molecule in the cell model used in this study is unlikely. All the n 3 PUFAs examined modulated fatty acid synthesis by decreasing the accumulation of SREBP 1c mRNA. None of the n 3 fatty acids used in this study altered the transcription of LDLR or SREBP 2, a potent regulator of the LDLR promoter, indicating that this pathway was not involved in the observed inhibition. While all the n 3 fatty acids examined resulted in equal inhibition of SREBP 1c and FASN (50 per cent reduction), they exhibited different efficiencies in the inhibition of proliferation. This suggested that alternative apoptotic or anti proliferative mechanisms needed to be invoked to cause the more substantial inhibitory trends observed following DHA and EPA treatment of PC 3 and LNCaP cells.
Taken together, these results may indicate that the different efficacies of the fatty acids examined in decreasing cell viability may be due to not only the modification of different pathways within androgen independent prostate cancer cells, but also to different magnitudes of response. (Editors comments)
