Title |
Mitochondrial β-Carotene 9′,10′ Oxygenase Modulates Prostate Cancer Growth via NF-κB Inhibition: A Lycopene-Independent Function
|
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Published in |
Molecular Cancer Research, October 2016
|
DOI | 10.1158/1541-7786.mcr-16-0075 |
Pubmed ID | |
Authors |
Xiaoming Gong, Raju Marisiddaiah, Susan Zaripheh, Doris Wiener, Lewis P. Rubin |
Abstract |
Despite numerous inquiries into protective roles of lycopene in prostate cancer (PCa) prevention or therapy, little is known about mechanisms by which lycopene or its metabolites inhibit PCa. The enzyme beta-carotene 9,10'-oxygenase (BCO2), which catalyzes asymmetric cleavage of several carotenoids, is the principal regulator of lycopene metabolism, but the range of BCO2 biological functions is incompletely understood. This study investigated expression and functional roles of BCO2 in human PCa. Expression of the bco2 gene is dramatically decreased in PCa tissue and in a range of PCa cell lines as compared to non-neoplastic prostate tissue and normal prostatic epithelial cells, respectively. Inhibition of DNA methyltransferase activity restored bco2 expression in PCa cell lines tested. Treatment with lycopene or its metabolite, apo-10-lycopenal, also increased bco2 expression and 31 reduced cell proliferation in androgen-sensitive cell lines, but lycopene neither altered bco2 expression nor cell growth in androgen-resistant cells. Notably, restoring bco2 expression in PCa cells inhibited cell proliferation and colony formation, irrespective of lycopene exposure. Exogenous expression of either wild-type BCO2 or a mutant (enzymatically inactive) BCO2 in PCa cells reduced nuclear factor kappa B (NF-B) activity and decreased NF-B nuclear translocation and DNA binding. Together, these results indicate epigenetic loss of BCO2 expression is associated with prostate cancer progression. Moreover, these findings describe previously unanticipated functions of BCO2 that are independent of its enzymatic role in lycopene metabolism. This study identifies BCO2 as a tumor suppressor in prostate cancer. BCO2-mediated inhibition of NF-kappaB signaling implies BCO2 status is important in prostate cancer progression. |
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