Heme oxygenase-1 inhibits rat and human breast cancer cell proliferation: mutual cross inhibition with indoleamine 2,3-dioxygenase
Heme oxygenase-1 inhibits rat and human breast cancer cell proliferation: mutual cross inhibition with indoleamine 2,3-dioxygenase
复制标题
DOI：
10.1096/fj.05-3875com
复制
发表时间：
2005-12-01
期刊：
影响因子：
4.8
通讯作者：
Anegon, I
中科院分区：
文献类型：
--
作者：
Hill, M;Pereira, V;Anegon, I
血红素加氧酶-1（HO-1）是血红素催化的限速酶，而吲哚胺2，3双加氧酶（IDO）通过犬尿氨酸途径分解代谢色氨酸。我们分析了这些酶在大鼠和人乳腺癌细胞系中的表达和生物学效应。我们发现，大鼠（NMU和13762），而不是人类细胞（MCF-7和T47 D）表达HO-1。当过表达时，我们发现这种酶在这四种细胞系中通过抗氧化机制具有抗增殖和促凋亡作用。我们发现IDO由大鼠和人乳腺癌细胞表达。用1-MT和siRNA抑制IDO导致大鼠细胞中增殖减少。相反，HO-1阴性人细胞系在IDO抑制后增加增殖。由于我们也证明了IDO抑制抗增殖HO-1，我们提出IDO对增殖具有相反的作用，这取决于HO-1的共表达与否。我们还描述了HO-1通过血红素饥饿在翻译后水平抑制IDO。在体内，我们发现，大鼠正常乳腺表达HO-1和IDO。相比之下，N-亚硝基甲脲诱导的乳腺腺癌仅表达IDO。总之，我们发现HO-1/IDO交叉调节调节大鼠和人乳腺癌细胞的凋亡和增殖。
Heme oxygenase-1 (HO-1) is the rate limiting enzyme of heme catabolism whereas indoleamine 2,3 dioxygenase (IDO) catabolizes tryptophan through the kynurenine pathway. We analyzed the expression and biological effects of these enzymes in rat and human breast cancer cell lines. We show that rat (NMU and 13762) but not human cells (MCF-7 and T47D) express HO-1. When overexpressed, we found this enzyme to have anti-proliferative and proapoptotic effects by antioxidant mechanisms in these four cell lines. We show that IDO is expressed by rat and human breast cancer cells. IDO inhibition with 1-MT and siRNA leads to diminished proliferation in rat cells. In contrast, HO-1 negative human cell lines increase proliferation upon IDO inhibition. Since we also demonstrate that IDO inhibits the anti-proliferative HO-1, we propose that IDO has opposite effects on proliferation depending on the coexpression or not of HO-1. We also describe that HO-1 inhibits IDO at the post-translational level through heme starvation. In vivo, we show that rat normal breast expresses HO-1 and IDO. In contrast, N-nitrosomethylurea-induced breast adenocarcinomas only express IDO. In conclusion, we show that HO-1/IDO cross-regulation modulates apoptosis and proliferation in rat and human breast cancer cells.