Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40536-0305, USA.
Toxicol Appl Pharmacol. 2013 Sep 1;271(2):239-48. doi: 10.1016/j.taap.2013.04.036. Epub 2013 May 22.
Cr(VI) compounds are known human carcinogens that primarily target the lungs. Cr(VI) produces reactive oxygen species (ROS), but the exact effects of ROS on the signaling molecules involved in Cr(VI)-induced carcinogenesis have not been extensively studied. Chronic exposure of human bronchial epithelial cells to Cr(VI) at nanomolar concentrations (10-100nM) for 3months not only induced cell transformation, but also increased the potential of these cells to invade and migrate. Injection of Cr(VI)-stimulated cells into nude mice resulted in the formation of tumors. Chronic exposure to Cr(VI) increased levels of intracellular ROS and antiapoptotic proteins. Transfection with catalase or superoxide dismutase (SOD) prevented Cr(VI)-mediated increases in colony formation, cell invasion, migration, and xenograft tumors. While chronic Cr(VI) exposure led to activation of signaling cascades involving PI3K/AKT/GSK-3β/β-catenin and PI3K/AKT/mTOR, transfection with catalase or SOD markedly inhibited Cr(VI)-mediated activation of these signaling proteins. Inhibitors specific for AKT or β-catenin almost completely suppressed the Cr(VI)-mediated increase in total and active β-catenin proteins and colony formation. In particular, Cr(VI) suppressed autophagy of epithelial cells under nutrition deprivation. Furthermore, there was a marked induction of AKT, GSK-3β, β-catenin, mTOR, and carcinogenic markers in tumor tissues formed in mice after injection with Cr(VI)-stimulated cells. Collectively, our findings suggest that ROS is a key mediator of Cr(VI)-induced carcinogenesis through the activation of PI3K/AKT-dependent GSK-3β/β-catenin signaling and the promotion of cell survival mechanisms via the inhibition of apoptosis and autophagy.
六价铬化合物是已知的人类致癌物，主要作用于肺部。六价铬会产生活性氧（ROS），但 ROS 对涉及六价铬诱导致癌作用的信号分子的确切影响尚未得到广泛研究。将人类支气管上皮细胞在纳米摩尔浓度（10-100nM）下慢性暴露于六价铬 3 个月，不仅诱导细胞转化，还增加了这些细胞侵袭和迁移的潜力。将六价铬刺激的细胞注射到裸鼠中会导致肿瘤形成。慢性暴露于六价铬会增加细胞内 ROS 和抗凋亡蛋白的水平。转染过氧化氢酶或超氧化物歧化酶（SOD）可防止六价铬介导的集落形成、细胞侵袭、迁移和异种移植物肿瘤增加。虽然慢性六价铬暴露会导致涉及 PI3K/AKT/GSK-3β/β-catenin 和 PI3K/AKT/mTOR 的信号级联的激活，但转染过氧化氢酶或 SOD 可显著抑制六价铬介导的这些信号蛋白的激活。针对 AKT 或 β-catenin 的抑制剂几乎完全抑制了六价铬介导的总和活性 β-catenin 蛋白和集落形成的增加。特别是，六价铬在营养剥夺下抑制了上皮细胞的自噬。此外，在用六价铬刺激的细胞注射后形成的小鼠肿瘤组织中，AKT、GSK-3β、β-catenin、mTOR 和致癌标志物的表达明显增加。总之，我们的研究结果表明，ROS 是六价铬诱导致癌作用的关键介质，通过激活 PI3K/AKT 依赖性 GSK-3β/β-catenin 信号以及通过抑制细胞凋亡和自噬来促进细胞存活机制。
