Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA-damaging agents
Scatter factor protects epithelial and carcinoma cells against apoptosis induced by DNA-damaging agents
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DOI：
10.1038/sj.onc.1201943
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发表时间：
1998-07-16
期刊：
影响因子：
8
通讯作者：
Rosen, EM
中科院分区：
文献类型：
--
作者：
Fan, SJ;Wang, JA;Rosen, EM
分散因子（SF）（肝细胞生长因子）是一种可能在人类乳腺癌侵袭和血管生成中发挥作用的细胞因子，我们现在报道SF可以阻断各种DNA损伤剂诱导的细胞凋亡，包括乳腺癌治疗中使用的细胞毒剂。 SF 保护 MDA-MB-453 人乳腺癌细胞、EMT6 小鼠乳腺肿瘤细胞和 MDCK 肾上皮细胞免受阿霉素 (ADR)、X 射线、紫外线辐射和其他药物诱导的细胞凋亡。在 DNA 碎片、细胞活力 (MTT) 和克隆存活的测定中观察到保护作用。 MDA-MB-453 细胞针对 ADR 的保护作用具有剂量和时间依赖性；最大保护需要用 75-100 ng/ml SF 预孵育 48 小时或更长时间。保护需要功能性 SF 受体 (c-Met)，但不依赖于 p53。 Western blotting 分析显示，用 SF 预处理 MDA-MB-453 细胞可抑制 ADR 诱导的 Bcl-X-L（一种与 Bcl-2 相关的抗凋亡蛋白）水平下降。 SF 介导的 ADR 处理细胞 Bcl-X-L 蛋白水平增加的剂量反应和时程特征与相同条件下观察到的细胞凋亡保护程度一致。此外，MDA-MB-231 乳腺癌细胞中的 Bcl-X-L 水平并未因 ADR 下调，这与 SF 未能保护这些细胞免受 ADR 侵害的发现一致，尽管它们含有功能性 c-Mrt 受体。与 Bcl-X-L 相比，SF 阻断 ADR 诱导的 c-Myc 增加，并抑制 MDA-MB-453 细胞中 p2(WAF1/CIP1) 和 BRCA1 蛋白的表达。然而，SF 并没有引起 ADR 处理细胞的细胞周期分布的显着变化。这些发现表明，SF介导的对人乳腺癌细胞的保护可能涉及抑制细胞凋亡激活所需的一种或多种途径，并且可能特别针对抗凋亡线粒体膜成孔蛋白Bcl-X-L作为保护机制的组成部分。这意味着，人类乳腺癌中 SF 的积累可能有助于放射或化学抗性表型的发展。
Scatter factor (SF) (hepatocyte growth factor) is a cytokine that may play a role in human breast cancer invasiveness and angiogenesis, We now report that SF can block the induction of apoptosis by various DNA damaging-agents, including cytotoxic agents used in breast cancer therapy. SF protected MDA-MB-453 human breast cancer cells, EMT6 mouse mammary tumor cells and MDCK renal epithelial cells against apoptosis induced by adriamycin (ADR), X-rays, ultraviolet radiation, and other agents. Protection was observed in assays of DNA fragmentation, cell viability (;MTT), and clonogenic survival. Protection of MDA-MB-453 cells against ADR was dose- and time-dependent; maximal protection required pre-incubation with 75-100 ng/ml of SF for 48 h or more. Protection required functional SF receptor (c-Met), but was not dependent on p53. Western blotting analysis revealed that pre-treatment of MDA-MB-453 cells with SF inhibited the ADR-induced decreases in the levels of Bcl-X-L, an anti-apoptotic protein related to Bcl-2; and the dose-response and time course characteristics for SF-mediated increases in the Bcl-X-L protein levels of ADR-treated cells were consistent with the degrees of protection against apoptosis observed under the same conditions. Furthermore, Bcl-X-L levels were not down-regulated by ADR in MDA-MB-231 breast cancer cells, consistent with the finding that SF failed to protect these cells against ADR, despite the fact that they contain functional c-Mrt receptor. In contrast to Bcl-X-L, SF blocked ADR-induced increases in c-Myc and inhibited the expression of p2(WAF1/CIP1) and of the BRCA1 protein in MDA-MB-453 cells. However, SF did not cause significant changes in the cell cycle distribution of ADR-treated cells. These findings suggest that SF-mediated protection of human breast cancer cells may involve inhibition of one or more pathways required for the activation of apoptosis and may particularly target the anti-apoptotic mitochondrial membrane pore-forming protein Bcl-X-L as a component of the protective mechanism. By implication, the accumulation of SF within human breast cancers may contribute to the development of a radio- or chemoresistant phenotype.