Effect of n3 and n6 unsaturated fatty acids on prostate cancer (PC3) and prostate epithelial
Effect of n3 and n6 unsaturated fatty acids on prostate cancer (PC3) and prostate epithelial
Year: 2013
Authors: Meng, H. Shen, Y. Shen, J. Zhou, F. Shen, S. Das, U.N.
Publication Name: Lipids Health Dis.
Publication Details: Volume12; Page 160
Abstract:
Prostate cancer (PCa) is one of the leading causes of death in the elderly men. Polyunsaturated fatty acids (PUFAs) regulate proliferation of cancer cells. In the present study, we evaluated the effect of various PUFAs on the proliferation and survival of human prostate cancer (PC 3) and human prostate epithelial (RWPE1) cells in vitro. LA, GLA, AA, ALA, EPA and DHA (linoleic acid, gamma linolenic acid, arachidonic acid, alpha linolenic acid, eicosapentaenoic acid and docosahexaenoic acid respectively) when tested at 50, 100, 150, and 200 microM inhibited proliferation of RWPE 1 and PC 3 cells, except that lower concentrations of LA (25 microM) and GLA (5, 10 microM) promoted proliferation. Though all fatty acids tested produced changes in the production of interleukin 6 (IL 6), tumor necrosis factor alpha (TNFalpha), lipoxin A4 and free radical generation by RWPE 1 and PC 3 cells, there were significant differences in their ability to do so. As expected, supplementation of various n 3 and n 6 fatty acids to RWPE 1 and PC 3 cells enhanced the content of the added fatty acids and their long chain metabolites in these cells. In contrast to previous results, we did not find any direct correlation between inhibition of cell proliferation induced by various fatty acids and free radical generation. These results suggest that polyunsaturated fatty acids suppress proliferation of normal and tumor cells by a variety of mechanisms that may partly depend on the type(s) of cell(s) being tested and the way these fatty acids are handled by the cells. Hence, it is suggested that more deeper and comprehensive studies are needed to understand the actions of fatty acids on the growth of normal and tumor cells. (Authors abstract)
Prostate cancer is one of the leading causes of cancer death among men in the United States. Compared to Eastern diet, Western diet contains higher levels of saturated fats, which may play a role in prostate cancer development. Several studies reported that n 3 PUFAs have an inverse association with prostate cancer, which showed that EPA and DHA suppressed human
prostate tumor cell growth. This could be related to the fact that EPA and DHA can displace AA from cell membrane phospholipids and suppress pro inflammatory prostaglandin synthesis. Epidemiological studies were inconclusive on the association between prostate cancer risk and intake of n 3 or n 6 PUFAs that are substrates for eicosanoid synthesis, with n 6 PUFAs being converted predominantly into pro inflammatory eicosanoids, while n 3 PUFAs being converted into anti inflammatory or less pro inflammatory eicosanoids. In order to understand the role of various PUFAs on the growth of normal and tumor cells, the effect of various PUFAs: LA, GLA, AA, ALA, EPA and DHA on the growth of RWPE 1 (human prostate epithelial cell) and PC 3 (human prostatic carcinoma cell) and their effects on fatty acid metabolism and ability to modulate the production of IL 6, TNFalpha, lipoxin A4 and free radical generation were studied. The present study showed that both n 3 (ALA, EPA, DHA) and n 6 PUFAs (LA, GLA, AA) suppress proliferation of both PC 3 and RWPE 1 cells, while these fatty acids at low concentrations had little influence on cell viability and even promoted their growth. RWPE 1 cells were more sensitive to the growth inhibitory actions of n 3 (ALA, EPA, and DHA) and n 6 fatty acids (LA, GLA, AA) in comparison to their effect on PC 3 cells, implying that RWPE 1 cells are more susceptible to the cytotoxic action of fatty acids compared to PC 3 cells.
Prostate cancer develops and progresses in response to inflammation during the cancer process. Several studies showed that a proinflammatory environment may be set in the prostate gland tissue when the balance between pro and anti-inflammatory PUFAs (n 6 PUFAs vs n 3 PUFAs) is tilted more towards the pro inflammatory (n 6 PUFAs) fatty acids. N 3 PUFAs: ALA, EPA and DHA have the ability to displace AA from the cell membrane phospholipids and suppress the production of pro inflammatory eicosanoids. The results of the present study showed that LA, ALA, EPA and DHA and LA GLA, AA, EPA and DHA decreased secretion of LXA4 by PC 3 cells and RWPE 1 cells respectively, while GLA enhanced and AA had very little effect on the secretion of LXA4 in PC 3 cells. These results suggest that, in general, most of the n 3 and n 6 fatty acids decrease LXA4 secretion by both normal and tumor cells with the exception of GLA and AA. These results underscore the complex nature of interaction among various PUFAs (both n 3 and n 6 PUFAs), their pro and anti inflammatory products (such as prostaglandins, leukotrienes and thromboxanes and lipoxins), local and systemic inflammatory process and the growth of prostate cancer cells. The results suggest that the local concentration of n 6 PUFAs can modulate the secretion of TNFalpha that, in turn, influence the local inflammatory process and consequently the process of carcinogenesis and growth of the tumor cells depending on the ratio among various n 6 PUFAs: LA, GLA and AA.
There were significant changes in the fatty acid composition of both RWPE 1 and PC 3 cells that were supplemented with various fatty acids. Supplementation ALA (both 50 and 150 microM) enhanced the content of ALA and EPA but notof DHA; EPA enhanced the content of both EPA and DHA; whereas DHA increased the content of only DHA in RWPE 1 cells significantly. RWPE 1 cells when were incubated with LA, a significant increase in the content of LA and GLA occurred with no change in that of AA; GLA induced a significant increase of GLA and AA; whereas supplementation of AA increased those of LA, GLA and AA. These results suggest that to certain extent, the supplemented fatty acids such as ALA, EPA and LA, and AA are metabolized to their long chain metabolites namely ALA to EPA and DHA; EPA to DHA; LA to GLA and GLA to AA. PC 3 cells supplemented with LA (especially with 150 microM) showed an increase in ALA, EPA and DHA with a concomitant significance increase in LA; while supplementation with GLA and AA (at all the doses tested) produced a significant increase in their content of AA (Table 2), suggesting that GLA is being elongated and desaturated to AA. GLA supplementation enhanced the ALA content of PC 3 cells with little or no change in EPA and DHA and if at all there is any change a decrease in their DHA content was noted, suggesting that GLA is able to block the conversion of ALA to its long chain metabolites EPA and DHA that could have enhanced its (PC 3 cells) ALA content. The precise mechanism by which n 3 and n 6 fatty acids are able to bring about their cell killing effect are not known since none of the indices studied (free radicals generated, changes in the levels of LXA4, IL 6 and TNF α secreted) showed any direct correlation among tumor cell survival and the indices studied, it is likely that several mechanism(s) may be at play that include generation of significant amounts of free radicals, formation of higher amounts of lipid peroxides in PUFA supplemented cells, changes in the formation and secretion of anti inflammatory cytokines and the response of cells to the growth enhancing potential of these cytokines, and the ability of these cells to secrete anti inflammatory bioactive lipids such as lipoxin A4. Further studies are needed to understand the mechanism(s) involved in the cytotoxic action of n 3 and n 6 fatty acids on prostate cancer cells and prostate normal cells. (Editors comments)
prostate tumor cell growth. This could be related to the fact that EPA and DHA can displace AA from cell membrane phospholipids and suppress pro inflammatory prostaglandin synthesis. Epidemiological studies were inconclusive on the association between prostate cancer risk and intake of n 3 or n 6 PUFAs that are substrates for eicosanoid synthesis, with n 6 PUFAs being converted predominantly into pro inflammatory eicosanoids, while n 3 PUFAs being converted into anti inflammatory or less pro inflammatory eicosanoids. In order to understand the role of various PUFAs on the growth of normal and tumor cells, the effect of various PUFAs: LA, GLA, AA, ALA, EPA and DHA on the growth of RWPE 1 (human prostate epithelial cell) and PC 3 (human prostatic carcinoma cell) and their effects on fatty acid metabolism and ability to modulate the production of IL 6, TNFalpha, lipoxin A4 and free radical generation were studied. The present study showed that both n 3 (ALA, EPA, DHA) and n 6 PUFAs (LA, GLA, AA) suppress proliferation of both PC 3 and RWPE 1 cells, while these fatty acids at low concentrations had little influence on cell viability and even promoted their growth. RWPE 1 cells were more sensitive to the growth inhibitory actions of n 3 (ALA, EPA, and DHA) and n 6 fatty acids (LA, GLA, AA) in comparison to their effect on PC 3 cells, implying that RWPE 1 cells are more susceptible to the cytotoxic action of fatty acids compared to PC 3 cells.
Prostate cancer develops and progresses in response to inflammation during the cancer process. Several studies showed that a proinflammatory environment may be set in the prostate gland tissue when the balance between pro and anti-inflammatory PUFAs (n 6 PUFAs vs n 3 PUFAs) is tilted more towards the pro inflammatory (n 6 PUFAs) fatty acids. N 3 PUFAs: ALA, EPA and DHA have the ability to displace AA from the cell membrane phospholipids and suppress the production of pro inflammatory eicosanoids. The results of the present study showed that LA, ALA, EPA and DHA and LA GLA, AA, EPA and DHA decreased secretion of LXA4 by PC 3 cells and RWPE 1 cells respectively, while GLA enhanced and AA had very little effect on the secretion of LXA4 in PC 3 cells. These results suggest that, in general, most of the n 3 and n 6 fatty acids decrease LXA4 secretion by both normal and tumor cells with the exception of GLA and AA. These results underscore the complex nature of interaction among various PUFAs (both n 3 and n 6 PUFAs), their pro and anti inflammatory products (such as prostaglandins, leukotrienes and thromboxanes and lipoxins), local and systemic inflammatory process and the growth of prostate cancer cells. The results suggest that the local concentration of n 6 PUFAs can modulate the secretion of TNFalpha that, in turn, influence the local inflammatory process and consequently the process of carcinogenesis and growth of the tumor cells depending on the ratio among various n 6 PUFAs: LA, GLA and AA.
There were significant changes in the fatty acid composition of both RWPE 1 and PC 3 cells that were supplemented with various fatty acids. Supplementation ALA (both 50 and 150 microM) enhanced the content of ALA and EPA but notof DHA; EPA enhanced the content of both EPA and DHA; whereas DHA increased the content of only DHA in RWPE 1 cells significantly. RWPE 1 cells when were incubated with LA, a significant increase in the content of LA and GLA occurred with no change in that of AA; GLA induced a significant increase of GLA and AA; whereas supplementation of AA increased those of LA, GLA and AA. These results suggest that to certain extent, the supplemented fatty acids such as ALA, EPA and LA, and AA are metabolized to their long chain metabolites namely ALA to EPA and DHA; EPA to DHA; LA to GLA and GLA to AA. PC 3 cells supplemented with LA (especially with 150 microM) showed an increase in ALA, EPA and DHA with a concomitant significance increase in LA; while supplementation with GLA and AA (at all the doses tested) produced a significant increase in their content of AA (Table 2), suggesting that GLA is being elongated and desaturated to AA. GLA supplementation enhanced the ALA content of PC 3 cells with little or no change in EPA and DHA and if at all there is any change a decrease in their DHA content was noted, suggesting that GLA is able to block the conversion of ALA to its long chain metabolites EPA and DHA that could have enhanced its (PC 3 cells) ALA content. The precise mechanism by which n 3 and n 6 fatty acids are able to bring about their cell killing effect are not known since none of the indices studied (free radicals generated, changes in the levels of LXA4, IL 6 and TNF α secreted) showed any direct correlation among tumor cell survival and the indices studied, it is likely that several mechanism(s) may be at play that include generation of significant amounts of free radicals, formation of higher amounts of lipid peroxides in PUFA supplemented cells, changes in the formation and secretion of anti inflammatory cytokines and the response of cells to the growth enhancing potential of these cytokines, and the ability of these cells to secrete anti inflammatory bioactive lipids such as lipoxin A4. Further studies are needed to understand the mechanism(s) involved in the cytotoxic action of n 3 and n 6 fatty acids on prostate cancer cells and prostate normal cells. (Editors comments)
