Over-expression of human endosulfatase-1 exacerbates cadmium-induced injury to transformed human lung cells in vitro.
Over-expression of human endosulfatase-1 exacerbates cadmium-induced injury to transformed human lung cells in vitro.
复制标题
人内硫酸酯酶 1 的过度表达会加剧镉诱导的体外转化人肺细胞损伤。
DOI：
10.1016/j.taap.2012.09.008
复制
发表时间：
2012
影响因子：
3.8
通讯作者：
Sannes,PhilipL
中科院分区：
文献类型：
--
作者：
Zhang,Huiying;Newman,DonnaR;Bonner,JamesC;Sannes,PhilipL
已知环境中暴露于镉会对肺的肺泡上皮细胞造成损伤，损害其修复能力，并导致永久性结构改变。细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）可以通过与可溶性效应分子的相互作用来调节细胞对损伤的反应。这些相互作用通常是硫酸盐特异性的，从HS侧链上去除硫酸盐基团可能会影响细胞损伤，例如暴露于镉引起的损伤。本研究的目的是确定6-O-硫酸盐在两种肺上皮癌细胞系（H292和A549）和正常人原代肺泡II型（hAT 2）细胞对镉暴露的细胞反应中所起的作用。硫酸盐水平通过6-O-内硫酸酯酶（HSulf-1）的转导瞬时过表达进行修饰，6-O-内硫酸酯酶是一种膜结合酶，可特异性地从HSPG侧链上去除6-O-硫酸酯基团。结果表明，镉在低浓度下降低hAT 2细胞的细胞活力并激活凋亡途径，但在癌细胞中没有。HSulf-1的过表达，相反，在H292和A549细胞中降低细胞活力和激活凋亡途径，但在hAT 2细胞中没有。当与镉结合时，HSulf-1过表达进一步降低了细胞活力，加剧了转化细胞中凋亡途径的激活，但没有增加hAT 2细胞的毒性。HSulf-1使这些癌细胞敏感并加剧镉诱导的损伤的发现表明，HSPG上的6-O-硫酸酯基团可能在保护免受某些环境毒物（如重金属）的影响方面发挥重要作用。
Environmental exposure to cadmium is known to cause damage to alveolar epithelial cells of the lung, impair their capacity to repair, and result in permanent structural alterations. Cell surface heparan sulfate proteoglycans (HSPGs) can modulate cell responses to injury through their interactions with soluble effector molecules. These interactions are often sulfate specific, and the removal of sulfate groups from HS side chains could be expected to influence cellular injury, such as that caused by exposure to cadmium. The goal of this study was to define the role 6-O-sulfate plays in cellular responses to cadmium exposure in two pulmonary epithelial cancer cell lines (H292 and A549) and in normal human primary alveolar type II (hAT2) cells. Sulfate levels were modified by transduced transient over-expression of 6-O-endosulfatase (HSulf-1), a membrane-bound enzyme which specifically removes 6-O-sulfate groups from HSPG side chains. Results showed that cadmium decreased cell viability and activated apoptosis pathways at low concentrations in hAT2 cells but not in the cancer cells. HSulf-1 over-expression, on the contrary, decreased cell viability and activated apoptosis pathways in H292 and A549 cells but not in hAT2 cells. When combined with cadmium, HSulf-1 over-expression further decreased cell viability and exacerbated the activation of apoptosis pathways in the transformed cells but did not add to the toxicity in hAT2 cells. The finding that HSulf-1 sensitizes these cancer cells and intensifies the injury induced by cadmium suggests that 6-O-sulfate groups on HSPGs may play important roles in protection against certain environmental toxicants, such as heavy metals.