Mitochondrial β-Carotene 9′, 10′ Oxygenase Modulates Prostate Cancer Growth via NF-κB Inhibition: A Lycopene-Independent Function
Mitochondrial β-Carotene 9′, 10′ Oxygenase Modulates Prostate Cancer Growth via NF-κB Inhibition: A Lycopene-Independent Function
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DOI：
10.1158/1541-7786.mcr-16-0075
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发表时间：
2016-10-01
影响因子：
5.2
通讯作者：
Rubin, Lewis P.
中科院分区：
文献类型：
--
作者：
Gong, Xiaoming;Marisiddaiah, Raju;Rubin, Lewis P.
尽管番茄红素在前列腺癌预防或治疗中的保护作用有许多研究，但对番茄红素或其代谢物抑制前列腺癌的机制知之甚少。β-胡萝卜素9 '，10'-加氧酶（BCO 2）催化几种类胡萝卜素的不对称裂解，是番茄红素代谢的主要调节剂，但BCO 2生物学功能的范围尚未完全了解。本研究探讨了BCO 2在人前列腺癌中的表达和功能作用。与非肿瘤性前列腺组织和正常前列腺上皮细胞相比，bco 2基因在前列腺癌组织和一系列前列腺癌细胞系中的表达显著降低。抑制DNA甲基转移酶活性恢复bco 2在前列腺癌细胞系中的表达。用番茄红素或其代谢物apo-10-番茄醛处理雄激素敏感细胞系，也能增加bco 2的表达，减少细胞增殖，但番茄红素既不改变bco 2的表达，也不改变雄激素抵抗细胞的细胞生长。值得注意的是，恢复bco 2在前列腺癌细胞中的表达抑制了细胞增殖和集落形成，与番茄红素暴露无关。在前列腺癌细胞中外源性表达野生型BCO 2或突变型（酶失活）BCO 2可降低NF-κ B活性，并降低NF-κ B核转位和DNA结合。总之，这些结果表明BCO 2表达的表观遗传丢失与前列腺癌进展相关。此外，这些研究结果描述了以前未预料到的功能，BCO 2是独立的酶的作用，在番茄红素metabolis.Implications：这项研究确定BCO 2作为一种肿瘤抑制剂在前列腺癌。BCO 2介导的NF-κ B信号传导抑制表明BCO 2状态在前列腺癌进展中很重要。
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 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 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-kappa B activity and decreased NF-kappa 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.Implications: This study identifies BCO2 as a tumor suppressor in prostate cancer. BCO2-mediated inhibition of NF-kappa B signaling implies BCO2 status is important in prostate cancer progression.