Bilirubin inhibits tumor cell growth via activation of ERK
Bilirubin inhibits tumor cell growth via activation of ERK
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DOI：
10.4161/cc.6.24.5022
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发表时间：
2007-12-15
期刊：
影响因子：
4.3
通讯作者：
Margreiter, Raimund
中科院分区：
文献类型：
--
作者：
Oellinger, Robert;Kogler, Pamela;Margreiter, Raimund
几十年来，胆红素被认为是血红素降解的潜在有毒废物，直到发现它是一种有效的抗氧化剂。从对人类的观察和实验研究中积累的数据表明，胆色素可能对某些疾病有保护作用。根据我们自己的观察，胆红素诱导细胞周期停滞异常增殖的血管平滑肌细胞和临床观察描述了癌症的发病率较低的健康个体与正常或血清胆红素水平略有升高，我们假设，胆红素可能抑制肿瘤细胞增殖在体外和体内。作为可能的效应物，我们分析了参与细胞周期进展和凋亡的关键蛋白。在体内，在用胆红素处理的携带HRT-18结肠癌异种移植物的BALB/c裸鼠中评估肿瘤生长。在体外，我们研究了胆红素对各种细胞系的影响，并使用蛋白质印迹法研究了胆红素对HRT-18细胞中肿瘤细胞增殖的作用所涉及的信号通路。胆红素在体内可有效抑制肿瘤细胞增殖，在体外可抑制细胞生长和促凋亡。负责该作用的信号级联反应涉及p53、p27的诱导、视网膜母细胞瘤肿瘤抑制蛋白的低磷酸化以及半胱天冬酶活化。这些作用依赖于ERK 1/2。我们的研究表明，胆红素可能通过干扰促癌信号通路在防御癌症中发挥作用。
Bilirubin for decades was considered a potentially toxic waste product of heme degradation until the discovery that it is a potent antioxidant. Accumulating data from observations in humans and experimental studies indicate that the bile pigment may be protective against certain diseases. Based on our own observations that bilirubin induces cell cycle arrest in abnormally proliferating vascular smooth muscle cells and clinical observations describing a lesser incidence of cancer in healthy individuals with high normal or slightly elevated serum bilirubin levels, we hypothesized that bilirubin might suppress tumor cell proliferation in vitro and in vivo. As possible effectors we analyzed key proteins that are involved in cell cycle progression and apoptosis. In vivo, tumor growth was assessed in BALB/c nude mice bearing HRT-18 colon cancer xenografts that were treated with bilirubin. In vitro, we investigated the effect of bilirubin on various cell lines and the signaling pathways involved in bilirubin action on tumor cell proliferation in HRT-18 cells using western blots. Bilirubin potently inhibited tumor cell proliferation in vivo and acted cytostatic and pro-apoptotic in vitro. The signaling cascades responsible for this action involved induction of p53, p27, hypophosphorylation of the retinoblastoma tumor suppressor protein as well as caspase activation. These effects were dependent on ERK 1/2. Our study demonstrates that bilirubin may play a role in the defense against cancer by interfering with pro-cancerogenic signaling pathways.