Up-regulation of cathepsin B expression and enhanced secretion in mitochondrial DNA-depleted osteosarcoma cells
Up-regulation of cathepsin B expression and enhanced secretion in mitochondrial DNA-depleted osteosarcoma cells
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DOI：
10.1042/bc20080043
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发表时间：
2009-01-01
影响因子：
2.7
通讯作者：
Arnould, Thierry
中科院分区：
文献类型：
--
作者：
Hamer, Isabelle;Delaive, Edouard;Arnould, Thierry
背景资料。mtDNA（线粒体DNA）突变损害氧化磷酸化，可以通过增加活性氧的产生和通过释放参与细胞运动和侵袭的蛋白质来促进致癌。另一方面，许多人类癌症都与几种蛋白酶和肝素酶的上调和分泌增加有关。在本研究中，我们试图确定mtDNA的缺失是否可以调节143B骨肉瘤细胞中某些溶酶体水解酶的表达和/或分泌，因为这些mtDNA缺失的细胞具有比亲本细胞更高程度的侵袭性。与亲代细胞相比，我们在缺乏mtDNA的143B细胞（rho(0) 143B细胞）的条件培养基中测量到更高的原athepsin B含量，以及细胞内组织蛋白酶B的特异性活性升高。此外，我们观察到转录因子NF-kappa B（核因子kappa B）在缺乏功能性线粒体的细胞中被激活。最后，我们证明了RNA干扰对NF-kappa B p65亚基的下调导致rho(0) 143B细胞中组织蛋白酶B的表达降低。NF-kappa B上调组织蛋白酶B，随后将其分泌到细胞外环境，这可能是先前报道的mtdna缺失的143B骨肉瘤细胞侵袭性的部分原因。
Background information. mtDNA (mitochondrial DNA) mutations that impair oxidative phosphorylation can contribute to carcinogenesis through the increased production of reactive oxygen species and through the release of proteins involved in cell motility and invasion. On the other hand, many human cancers are associated with both the up-regulation and the increased secretion of several proteases and heparanase. In the present study, we tried to determine whether the depletion in mtDNA could modulate the expression and/or the secretion of some lysosomal hydrolases in the 143B osteosarcoma cells, as these mtDNA-depleted cells are characterized by a higher degree of invasiveness than the parental cells.Results. In comparison with the parental cells, we measured a higher amount of procathepsin B in the conditioned culture medium of the 143B cells lacking mtDNA (rho(0) 143B cells), as well as a rise in the specific activity of intracellular cathepsin B. In addition, we observed an activation of the transcription factor NF-kappa B (nuclear factor kappa B) in the cells devoid of functional mitochondria. Finally, we demonstrated that the down-regulation of the NF-kappa B p65 subunit by RNA interference led to a reduction in cathepsin B expression in rho(0) 143B cells.Conclusions. The up-regulation of cathepsin B by NF-kappa B, followed by its secretion into the extracellular environment, might be partly responsible for the previously reported invasiveness of the mtDNA-depleted 143B osteosarcoma cells.