| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
|
FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online November 15, 2004 as doi:10.1096/fj.04-1905fje. |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
DSM Nutritional Products, Human Nutrition and Health, Carotenoid Section, Basel, Switzerland
3 Correspondence: DSM Nutritional Products, Carotenoid Section, P.O. Box 3255, Basel CH-4002, Switzerland. E-mail: karin.wertz{at}dsm.com
SPECIFIC AIMS
Epidemiology has established a link between consumption of lycopene, the red carotenoid in tomato, and reduced prostate cancer risk. We investigated the effect of lycopene on gene regulation in normal prostate tissue of Copenhagen rats to identify mechanisms by which this nutrient could contribute to primary prevention of prostate cancer risk.
PRINCIPAL FINDINGS
Forty-two male Copenhagen rats were randomly assigned to treatment groups. The placebo group (n=8) received a basal diet containing 40 ppm vitamin E (originating from placebo formulation), a reduced vitamin A content (4000 IU/kg), and devoid of phytosterols. Lycopene-treated animals were fed basal diet enriched with 200 ppm lycopene. Starting at day 0 of supplementation, every 2 wk, a group of 6–8 lycopene-supplemented animals was killed. Eight wk after start of supplementation, eight lycopene-fed rats and eight placebo-fed rats were killed. For each animal, one lobe per prostate lobe pair (anterior, dorsal, lateral, and ventral) was used to quantify accumulation of lycopene isomers all-trans, 5-cis, 9-cis, and 13-cis lycopene by HPLC. In animals supplemented for 8 wk, gene expression was assessed individually in the other lobe of the dorsal and lateral prostate lobe pair using one chip per lobe and animal. Gene regulations in key pathways were confirmed by TaqMan® real-time RT-PCR.
1. Lycopene was taken up in prostate tissue and did not interfere with normal prostate growth
During 8 wk of supplementation total prostate lycopene content increased gradually and reached an average total lycopene concentration of 0.46 ± 0.091 nmol/g, with all-trans lycopene being the predominant isoform (59.8±5.7%). Lycopene uptake was lobe-specific, with highest total lycopene concentrations (0.78±0.07 nmol/g) in the lateral lobe. Isomer distribution was similar for all prostate lobes. Prostate lobe weights were not influenced by lycopene uptake.
2. Lycopene targeted local steroid metabolism, IGF-I expression, and inflammatory signals in normal prostate
Dorsal and lateral prostate lobes are considered the rat equivalent for the human peripheral zone, from which human prostate cancer primarily arises. Hence, we analyzed lycopene-induced gene regulations in these two lobes.
GeneChip® analysis revealed that overall lycopene had a mild but statistically significant effect on gene expression. The most important effects with respect to primary prostate cancer prevention were observed in local steroid metabolism and signaling, in local IGF-I expression, and in expression of inflammatory markers (Table 1
). Thus, lycopene regulated the same mechanisms in normal prostate, as recently identified in our previous study of rat prostate tumors.
|
Changes in expression profiles (Table 1)
of three major enzymes of androgen metabolism [5
-reductase, 17ß-hydroxysteroid-dehydrogenases (17ß-HSD), Cyp7B1] suggested that lycopene supplementation reduced activation of androgens in normal prostate tissue and therefore may have a beneficial effect on prostate cancer.
5-Reductase is responsible for conversion of androstenedione and testosterone (T) into the most potent natural androgen 5-dihydrotestosterone (5-DHT). 5-Reductase 2 was mildly but consistently down-regulated by lycopene in both lobes [fold induction, dorsal (fi-d): 0.66, fi-l: 0.81], indicating reduced androgen activation. This conclusion is supported by down-regulation of androgen targets (prostatic steroid binding protein C1 and C3, cystatin-related protein 2, and seminal vesicle secretion protein IV). This observation was reproduced by TaqMan® RT-PCR and confirmed our recent results in a rat prostate cancer tumor model.
17ß-HSD type IV is responsible for DHEA generation whereas Cyp7B1 regulates 3ßAdiol catabolism. Both DHEA and 3ßAdiol are ligands for estrogen receptor ß (ERß). Up-regulation of 17ß-HSD type IV (fi-d:1.55) as well as down-regulation of Cyp7B1 (fi-d: 0.66, fi-l:0.74) by lycopene indicates increased formation of both ERß ligands, presumably at the expense of 5-DHT formation. Selective ERß ligands have a crucial role in controlling proliferation of prostate epithelium and of prostate size, and are therefore used as agents to prevent or treat prostate cancer.
Similar to our recently published findings in the prostate tumor model, lycopene reduced IGF-I expression in normal prostate tissue. Down-regulation of local IGF-I expression (fi-d: 0.43, fi-l: 0.6) by lycopene was verified by TaqMan® RT-PCR. Elevated IGF-I expression is linked with increased risk for several types of cancer, including prostate cancer. Therefore, down-regulation of local IGF-I expression in prostate tissue indicates that lycopene interferes with endocrine/paracrine IGF-I signaling in prostate tissue.
Inflammatory markers, such as interleukin-1ß (IL-1ß), and CXC chemokines MIP-2 and LIX were significantly down-regulated by lycopene and indicated an anti-inflammatory action of lycopene. Moreover, some transcripts encoding immunoglobulins and immunoglobulin Fc receptor were less abundant in prostate tissue after lycopene supplementation, suggesting an anti-inflammatory effect of lycopene. Microarray results for MIP-2, LIX, IL-1ß, and the Fc receptor were confirmed by TaqManTM RT-PCR. These results are in line with the down-regulation of IL-6 by lycopene found in rat prostate tumors, since the above-mentioned cytokines regulate IL-6 transcription via the NF-
B pathway. Members of the NF-B pathway were either not included on the GeneChip® or not regulated. Chronic prostatitis is likely linked with increased prostate cancer risk. Therefore, in addition to the mechanisms mentioned above, lycopene may also inhibit prostate cancer development by an anti-inflammatory action in prostate.
CONCLUSIONS
Lycopene was taken up into all four prostate lobes, with the lateral lobe accumulating the highest lycopene concentrations. All-trans lycopene was the major isoform and represented 
60% of total lycopene content. Lycopene did not interfere with normal prostate growth. Lycopene uptake into prostate tissue resulted in significant changes in gene expression. Lycopene reduced local prostatic androgen signaling, IGF-I expression, and inflammatory responses. In summary, lycopene targeted in normal prostate the same pathways, all of which are crucially involved in prostate cancer pathogenesis, as in prostate tumors. The degree of regulation differed between the two models, with the anti-androgen effect being milder and the anti-inflammatory effect of lycopene being stronger in normal prostate tissue, as found in prostate tumors. The mechanisms identified can explain how dietary lycopene may reduce prostate cancer risk.
|
|
FOOTNOTES
1 These authors contributed equally to this work. 
2 Present address: Frimorfo, Fribourg, Switzerland
To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.04-1905fje;
This article has been cited by other articles:
|
|
 |
|
  X. Liu, J. D. Allen, J. T. Arnold, and M. R. Blackman Lycopene inhibits IGF-I signal transduction and growth in normal prostate epithelial cells by decreasing DHT-modulated IGF-I production in co-cultured reactive stromal cells Carcinogenesis, April 1, 2008; 29(4): 816 - 823. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Schwarz, U. C. Obermuller-Jevic, E. Hellmis, W. Koch, G. Jacobi, and H.-K. Biesalski Lycopene Inhibits Disease Progression in Patients with Benign Prostate Hyperplasia J. Nutr., January 1, 2008; 138(1): 49 - 53. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Vrieling, D. W Voskuil, J. M Bonfrer, C. M Korse, J. van Doorn, A. Cats, A. C Depla, R. Timmer, B. J Witteman, F. E van Leeuwen, et al. Lycopene supplementation elevates circulating insulin-like growth factor binding protein-1 and -2 concentrations in persons at greater risk of colorectal cancer Am. J. Clinical Nutrition, November 1, 2007; 86(5): 1456 - 1462. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. N. Syed, N. Khan, F. Afaq, and H. Mukhtar Chemoprevention of Prostate Cancer through Dietary Agents: Progress and Promise Cancer Epidemiol. Biomarkers Prev., November 1, 2007; 16(11): 2193 - 2203. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Giovannucci Does Prostate-Specific Antigen Screening Influence the Results of Studies of Tomatoes, Lycopene, and Prostate Cancer Risk? J Natl Cancer Inst, July 18, 2007; 99(14): 1060 - 1062. [Full Text] [PDF]
|
|
|
|
 |
|
 K. Canene-Adams, B. L. Lindshield, S. Wang, E. H. Jeffery, S. K. Clinton, and J. W. Erdman Jr. Combinations of Tomato and Broccoli Enhance Antitumor Activity in Dunning R3327-H Prostate Adenocarcinomas Cancer Res., January 15, 2007; 67(2): 836 - 843. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. K. Campbell, C. K. Stroud, M. T. Nakamura, M. A. Lila, and J. W. Erdman Jr. Serum Testosterone Is Reduced Following Short-Term Phytofluene, Lycopene, or Tomato Powder Consumption in F344 Rats J. Nutr., November 1, 2006; 136(11): 2813 - 2819. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
X. Zhao, G. Aldini, E. J Johnson, H. Rasmussen, K. Kraemer, H. Woolf, N. Musaeus, N. I Krinsky, R. M Russell, and K.-J. Yeum Modification of lymphocyte DNA damage by carotenoid supplementation in postmenopausal women Am. J. Clinical Nutrition, January 1, 2006; 83(1): 163 - 169. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Zaripheh and J. W. Erdman Jr. The Biodistribution of a Single Oral Dose of [14C]-Lycopene in Rats Prefed Either a Control or Lycopene-Enriched Diet J. Nutr., September 1, 2005; 135(9): 2212 - 2218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
U. Siler, A. Herzog, V. Spitzer, N. Seifert, A. Denelavas, P. B. Hunziker, L. Barella, W. Hunziker, M. Lein, R. Goralczyk, et al. Lycopene Effects on Rat Normal Prostate and Prostate Tumor Tissue J. Nutr., August 1, 2005; 135(8): 2050S - 2052S. [Full Text] [PDF]
|
|
|
|
|
|
P. E. Bowen Selection of Surrogate Endpoint Biomarkers to Evaluate the Efficacy of Lycopene/Tomatoes for the Prevention/Progression of Prostate Cancer J. Nutr., August 1, 2005; 135(8): 2068S - 2070S. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
