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The Role of Tomato Bioactive Components and CMO2 Gene Interaction in Prostate Cancer Prevention

Tan, Hsueh-Li
http://rave.ohiolink.edu/etdc/view?acc_num=osu1345493048

Abstract Details

2012, Doctor of Philosophy, Ohio State University, Nutrition Program, The Ohio State University.
Accumulating evidence suggests an inverse association between the consumption of lycopene rich tomato products and the risk of prostate cancer. Our central objective is to investigate the roles of tomato components, with a focus upon lycopene, on prostate biology and prostate carcinogenesis in rodent models. The study of diet and prostate carcinogenesis must consider the potential interactions with testosterone, an essential hormone for prostate function and carcinogenesis. We randomized TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) and wild type (WT) mice to hormone treatments: Intact, Castration, Castration + Testosterone Dose 2.5, or Dose 5.0. We observed that prostate proliferation and apoptosis were testosterone and genotype dependent. Evaluation of p53 signaling (PCR array) elucidated the gene expression patterns impacted by hormone and genotype. Multiple genes relevant to proliferation/cell survival/apoptosis were modulated by genotype and testosterone, for example, Birc5 was stimulated by testosterone (<0.001) and TRAMP genotype (<0.001). These genes may serve as potential biomarkers in early prostate carcinogenesis. C57/BL6 mice then fed either control AIN93-G, tomato, or lycopene. Mice were randomized to the same androgen groups without Dose 5.0. NanoString® gene analysis examined a molecular signature mediated by diet and hormone. Tomato and lycopene-fed intact mice showed reduced prostate proliferation by >50% (<0.001). A 30% inhibition (tomato, =0.02; lycopene, <0.001) was observed in the castrate-testosterone treated mice. Castration reduced proliferation by 60 % and enhanced apoptosis by 53% (main effect, =0.002). Diet and testosterone interacted to modulate growth factor signaling pathways such as IGF-Akt-mTOR pathway. Overall, tomato phytochemicals antagonize some of the pro-carcinogenic effects of testosterone in the prostate. Recently discovered genes (CMO1 and CMO2) are hypothesized to metabolize carotenoids. CMO2 potentially metabolizes lycopene by eccentric cleavage which could either produce active metabolites or initiate degradation. WT and CMO2 KO mice were fed control, tomato, or lycopene for 3 weeks. Tissue carotenoids were analyzed and hepatic gene expression was assessed (nuclear receptor and stress/toxicity arrays). CMO2 KO resulted in increases in serum and liver lycopene (=0.03). Hepatic Nr1d1 (circadian rhythm) expression was increased in tomato (vs. control: 3.9-fold) and lycopene (vs. control: 2.8-fold) mice (<0.0001), yet expression in CMO2 KO mice was increased by 487% in tomato fed mice but remained at 128% for lycopene. Conclusively, CMO2 is one enzyme that impacts lycopene metabolism. Tomato phytochemicals impact hepatic genes involved in metabolism. We also examine the impact of CMO2 KO on the anti-cancer effects of tomato/lycopene on TRAMP carcinogenesis. We randomized novel TRAMP: CMO2 WT and KO transgenic mice to diets (control, tomato, lycopene) for 15 weeks. We again confirmed that the CMO2 KO resulted in accumulation of lycopene and precursors in serum. Dietary tomato and lycopene ameliorated the worst prostate lesions and most common lesions (tomato: High-grade PIN/Moderate-grade PIN; Lycopene: High-grade PIN/ Moderate-grade PIN) compared to control fed mice (well differentiated adenocarcinoma/High-grade PIN) (<0.001). Preliminary data suggest that CMO2 depleted mice fed lycopene have less aggressive cancer phenotpye Overall, we demonstrate that dietary tomato and lycopene inhibit prostatic carcinogenesis. This works supports future human clinical trials intervening with tomato-based food products.
Steven Clinton (Advisor)

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Citations

  • Tan, H.-L. (2012). The Role of Tomato Bioactive Components and CMO2 Gene Interaction in Prostate Cancer Prevention [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1345493048

    APA Style (7th edition)

  • Tan, Hsueh-Li. The Role of Tomato Bioactive Components and CMO2 Gene Interaction in Prostate Cancer Prevention. 2012. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1345493048.

    MLA Style (8th edition)

  • Tan, Hsueh-Li. "The Role of Tomato Bioactive Components and CMO2 Gene Interaction in Prostate Cancer Prevention." Doctoral dissertation, Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1345493048

    Chicago Manual of Style (17th edition)

osu1345493048
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© 2012, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.
Release 3.2.12