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首页> 外文期刊>Archives of Toxicology >Endosomes and lysosomes are involved in early steps of Tl(III)-mediated apoptosis in rat pheochromocytoma (PC12) cells
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Endosomes and lysosomes are involved in early steps of Tl(III)-mediated apoptosis in rat pheochromocytoma (PC12) cells

机译：内体和溶酶体参与Tl（III）介导的大鼠嗜铬细胞瘤（PC12）细胞凋亡的早期阶段

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The mechanisms that mediate thallium (Tl) toxicity are still not completely understood. The exposure of rat pheochromocytoma (PC12) cells to Tl(I) or Tl(III) activates both mitochondrial (Tl(I) and Tl(III)) and extrinsic (Tl(III)) pathways of apoptosis. In this work we evaluated the hypothesis that the effects of Tl(III) may be mediated by the damage to lysosomes, where it might be incorporated following the route of iron uptake. PC12 cells exposed for 3 h to 100 μM Tl(III) presented marked endosomal acidification, effect that was absent when cells were incubated in a serum-free medium and that was fully recovered when the latter was supplemented with transferrin. After 6 h of incubation the colocalization of cathepsins D and B with the lysosomal marker Lamp-1 was decreased together with an increase in the total activity of the enzymes. A permanent damage to lysosomes after 18 h of exposure was evidenced from the impairment of acridine orange uptake. Cathepsin D caused the cleavage of pro-apoptotic protein BID that is involved in the activation of the intrinsic pathway of apoptosis. Supporting that, BID cleavage and the activation of caspase 3 by Tl(III) were fully prevented when cells were preincubated with cathepsin D inhibitor (pepstatin A) and only partially prevented when cathepsin B inhibitor (E64d) was used. None of these inhibitors affected BID cleavage or caspase 3 activation in Tl(I)-treated cells. Together, experimental results support the role of Tl(III) uptake by the acidic cell compartments and their involvement in the early steps of Tl(III)-mediated PC12 cells apoptosis.
机译：介导al（T1）毒性的机制仍不完全清楚。大鼠嗜铬细胞瘤（PC12）细胞暴露于Tl（I）或Tl（III）会激活线粒体（Tl（I）和Tl（III））和外源性（Tl（III））细胞凋亡途径。在这项工作中，我们评估了以下假设：Tl（III）的影响可能是由溶酶体的损害介导的，在溶酶体中铁可能通过铁的摄取途径而被掺入。暴露于100μMTl（III）3 h的PC12细胞呈现出明显的内体酸化作用，这种作用在无血清培养基中孵育时不存在，而当后者补充有转铁蛋白时可以完全恢复。温育6小时后，组织蛋白酶D和B与溶酶体标记Lamp-1的共定位减少，同时酶的总活性增加。 a啶橙摄入量的减少证明了暴露18 h后对溶酶体的永久性损害。组织蛋白酶D引起促凋亡蛋白BID的裂解，该蛋白参与凋亡内在途径的激活。支持这一点的是，当将细胞与组织蛋白酶D抑制剂（pepstatin A）预孵育时，T1（III）的BID裂解和caspase 3的激活被完全阻止，而当使用组织蛋白酶B抑制剂（E64d）时仅被部分阻止。这些抑制剂均未影响T1（I）处理的细胞中的BID裂解或caspase 3活化。总之，实验结果支持酸性细胞区室吸收Tl（III）的作用，并参与Tl（III）介导的PC12细胞凋亡的早期步骤。

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