Ollinger Robert, Kogler Pamela, Troppmair Jakob, Hermann Martin, Wurm Martin, Drasche Astrid, Königsrainer Ingmar, Amberger Albert, Weiss Helmut, Ofner Dietmar, Bach Fritz H, Margreiter Raimund
Department of General and Transplant Surgery, D. Swarovski Research Lab, Innsbruck Medical University, Innsbruck, Austria.
Cell Cycle. 2007 Dec 15;6(24):3078-85. doi: 10.4161/cc.6.24.5022. Epub 2007 Sep 7.
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.
几十年来，胆红素一直被认为是血红素降解产生的一种潜在有毒废物，直到发现它是一种强大的抗氧化剂。来自人体观察和实验研究的越来越多的数据表明，这种胆色素可能对某些疾病具有保护作用。基于我们自己的观察结果，即胆红素可诱导异常增殖的血管平滑肌细胞发生细胞周期停滞，以及临床观察结果表明，血清胆红素水平正常偏高或略有升高的健康个体患癌症的几率较低，我们推测胆红素可能在体外和体内抑制肿瘤细胞增殖。作为可能的效应物，我们分析了参与细胞周期进程和细胞凋亡的关键蛋白。在体内，我们评估了用胆红素处理的携带HRT-18结肠癌异种移植瘤的BALB/c裸鼠的肿瘤生长情况。在体外，我们使用蛋白质印迹法研究了胆红素对各种细胞系的影响以及胆红素作用于HRT-18细胞肿瘤细胞增殖所涉及的信号通路。胆红素在体内能有效抑制肿瘤细胞增殖，在体外具有细胞抑制和促凋亡作用。负责这种作用的信号级联反应包括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激活。这些效应依赖于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抗癌防御中发挥作用。
