Oh Jin-Mi, Ryoo In-Ja, Yang Young, Kim Hyun-Sun, Yang Kyu-Hwan, Moon Eun-Yi
Department of Bioscience and Biotechnology, Sejong University, Seoul, Republic of Korea.
Cancer Lett. 2008 Jun 8;264(1):29-35. doi: 10.1016/j.canlet.2008.01.004. Epub 2008 Feb 12.
Thymosin beta-4 (TB4) is an actin-sequestering protein to control cytoskeletal reorganization. Here, we investigated whether TB4 proteins (TB4P) affect tumor microenvironment by measuring hypoxia-inducible transcription factor (HIF)-1 alpha stabilization in cervical tumor cells, since TB4P reduced paclitaxel-induced cell death rate. TB4P increased HIF-1 alpha stabilization and transactivation, which is measured by the increase of hypoxia response element (HRE)-luciferase activity and target gene, vascular endothelial growth factor (VEGF) transcription. TB4P also elevated ERK phosphorylation. PD98059, ERK inhibitor reduced HIF-1 alpha increased by TB4P. Paclitaxel-induced cell death was inhibited by hypoxia conditioning that increased HIF-1 alpha stabilization and ERK phosphorylation. PD98059 reversed paclitaxel-induced cell death which was attenuated by hypoxia. Collectively, TB4P could lead tumor cell microenvironment to hypoxia condition, which might be resulted in antitumor drug-resistance induction. It suggests that soluble TB4P could be a novel target to control tumor cell death by regulating tumor cell microenvironment.
胸腺素β-4（TB4）是一种肌动蛋白隔离蛋白，可控制细胞骨架重组。在此，我们研究了胸腺素β-4蛋白（TB4P）是否通过测量宫颈肿瘤细胞中缺氧诱导转录因子（HIF）-1α的稳定性来影响肿瘤微环境，因为TB4P降低了紫杉醇诱导的细胞死亡率。TB4P增加了HIF-1α的稳定性和反式激活，这通过缺氧反应元件（HRE）-荧光素酶活性的增加以及靶基因血管内皮生长因子（VEGF）转录来衡量。TB4P还提高了ERK磷酸化水平。ERK抑制剂PD98059降低了TB4P所增加的HIF-1α水平。缺氧预处理增加了HIF-1α的稳定性和ERK磷酸化，从而抑制了紫杉醇诱导的细胞死亡。PD98059逆转了缺氧减弱的紫杉醇诱导的细胞死亡。总体而言，TB4P可使肿瘤细胞微环境处于缺氧状态，这可能导致抗肿瘤药物耐药性的产生。这表明可溶性TB4P可能是通过调节肿瘤细胞微环境来控制肿瘤细胞死亡的新靶点。
