Department of Pathology, Zhujiang Hospital, Southern Medical University, Guangzhou, China.
Exp Mol Pathol. 2010 Jun;88(3):401-6. doi: 10.1016/j.yexmp.2010.02.003. Epub 2010 Mar 4.
Epithelial and endothelial tyrosine kinase (Etk), also known as Bmx (bone marrow X kinase) plays an important role in apoptosis of epithelial cells. The goal of this study was to investigate whether Etk is involved in apoptosis of small cell lung cancer (SCLC) cells and correlated with the expression levels of apoptosis-associated proteins such as Bcl-2, Bcl-X(L) and p53. One hundred and seventy-one cases of lung cancer specimens including seventy-one SCLCs and one hundred NSCLCs were immunostained for Etk, Bcl-2, Bcl-X(L) and p53. Parental SCLC H446 cell line, and its subline (H446-Etk) that overexpresses Etk, were used to study the role of Etk in apoptosis induced by doxorubicin. It was found that high expression of Etk occurs in 74.6% of SCLC cases, but only in 40% of NSCLC cases, and there is marked difference in the expression levels of Bcl-2, Bcl-X(L) and p53 between Etk-positive and Etk-negative SCLC cases. Furthermore, the levels of Bcl-2 and Bcl-X(L) significantly increased in H446-Etk cells than that in H446 cells after doxorubicin treatment, and were positively associated with Etk expression. However, p53 did not correspond with Etk expression although its expression decreased greatly with apoptosis both in H446-Etk and H446 cells. After doxorubicin treatment, the cell viability was significantly higher in H446-Etk cells than in parental H446 cells. Downregulation of Etk by Etk siRNA sensitized H446 cells to doxorubicin. Our results indicate that upregulation of tyrosine kinase Etk may be a new mechanism involved in protection of SCLC cells from apoptosis. Bcl-2 and Bcl-X(L) but not p53 may contribute to doxorubicin-induced apoptosis through Etk pathway.
上皮和内皮酪氨酸激酶 (Etk)，也称为 Bmx（骨髓 X 激酶），在上皮细胞凋亡中发挥重要作用。本研究的目的是探讨 Etk 是否参与小细胞肺癌 (SCLC) 细胞的凋亡，并与凋亡相关蛋白如 Bcl-2、Bcl-X(L) 和 p53 的表达水平相关。对 171 例肺癌标本（包括 71 例 SCLC 和 100 例 NSCLC）进行 Etk、Bcl-2、Bcl-X(L) 和 p53 的免疫染色。使用亲本 SCLC H446 细胞系及其过表达 Etk 的亚系 (H446-Etk) 研究 Etk 在多柔比星诱导的凋亡中的作用。结果发现，Etk 在 74.6%的 SCLC 病例中高表达，但在 40%的 NSCLC 病例中仅低表达，且 Etk 阳性和 Etk 阴性 SCLC 病例的 Bcl-2、Bcl-X(L) 和 p53 表达水平存在显著差异。此外，多柔比星处理后，H446-Etk 细胞中 Bcl-2 和 Bcl-X(L) 的水平明显高于 H446 细胞，且与 Etk 表达呈正相关。然而，p53 与 Etk 表达不对应，尽管其在 H446-Etk 和 H446 细胞中凋亡时表达显著下调。多柔比星处理后，H446-Etk 细胞的细胞活力明显高于亲本 H446 细胞。Etk siRNA 下调 Etk 可使 H446 细胞对多柔比星敏感。我们的结果表明，酪氨酸激酶 Etk 的上调可能是 SCLC 细胞免于凋亡的新机制。Bcl-2 和 Bcl-X(L) 而不是 p53 可能通过 Etk 途径促进多柔比星诱导的凋亡。
