Mitochondrial β-Carotene 9′,10′ Oxygenase Modulates Prostate Cancer Growth via NF-κB Inhibition: A Lycopene-Independent Function

Abstract

Despite numerous inquiries into protective roles of lycopene in prostate cancer prevention or therapy, little is known about mechanisms by which lycopene or its metabolites inhibit prostate cancer. The enzyme b-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 prostate cancer. Expression of the bco2 gene is dramatically decreased in prostate cancer tissue and in a range of prostate cancer cell lines as compared with nonneoplastic prostate tissue and normal prostatic epithelial cells, respectively. Inhibition of DNA methyltransferase activity restored bco2 expression in prostate cancer cell lines tested. Treatment with lycopene or its metabolite, apo-10-lycopenal, also increased bco2 expression and 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 prostate cancer 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 prostate cancer cells reduced NF-kB activity and decreased NF-kB 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.

β-Carotene 9′,10′ Oxygenase Modulates the Anticancer Activity of Dietary Tomato or Lycopene on Prostate Carcinogenesis in the TRAMP Model

“…In the TRAMP mice fed a control AIN diet, we do not detect an impact of Bco2−/− compared to Bco2+/+ genotype. There is new evidence that exogenous Bco2 expression leads to inhibition of prostate cancer cell growth in vitro , in a lycopene- and enzyme activity-independent manner, (59) highlighting a potential BCO2 function in prostatic tissue, that was not detectable in the TRAMP system designed to test prevention. When fed tomato or lycopene, we see an attenuation of the anticancer effect in the Bco2−/− compared to Bco2+/+ mice.…”

The Biochemistry and Antioxidant Properties of Carotenoids

“…It was proposed that there is an inverse association between the occurrence of pancreatic cancer and dietary lycopene intake together with vitamin A and β-carotene [70]. β-Carotene 9′,10′-oxygenase which is a key enzyme for the metabolism of lycopene has been proposed to have an important roles to prevent prostate cancer progression by inhibiting NF-κB signaling [71].…”

Lack of β, β‐carotene‐9′, 10′‐oxygenase 2 leads to hepatic mitochondrial dysfunction and cellular oxidative stress in mice

“…Variants at the BCO2 locus are associated with the IL-18 level, but not carotenoids in either plasma or macula (20). Studies have revealed that mutations in human BCO2 have been linked to macular degeneration (21), insulin resistance and obesity (22), and prostate cancer (23). Further, the loss of BCO2 protein expression is associated with the development of anemia in zebrafish, though the anemia results not from impaired erythropoiesis, but instead from increased apoptosis of erythrocyte precursors (24).…”