Prosaposin down-modulation decreases metastatic prostate cancer cell adhesion, migration, and invasion.
Prosaposin down-modulation decreases metastatic prostate cancer cell adhesion, migration, and invasion.
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DOI：
10.1186/1476-4598-9-30
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发表时间：
2010-02-04
期刊：
影响因子：
37.3
通讯作者：
Koochekpour S
中科院分区：
文献类型：
--
作者：
Hu S;Delorme N;Liu Z;Liu T;Velasco-Gonzalez C;Garai J;Pullikuth A;Koochekpour S
前列腺癌（PCa）侵袭性和转移性进展的因素在很大程度上仍然未知。在此之前，我们报道了鞘脂激活蛋白原（PSAP）的克隆及其在几种雄激素非依赖性转移性前列腺癌细胞系和淋巴结转移中的基因组扩增和/或过表达。PSAP是saposins的溶酶体前体，saposins充当参与神经酰胺（Cer）和其他鞘脂降解的溶酶体水解酶的激活剂。我们目前的数据表明，在转移性前列腺癌细胞中，通过溶酶体蛋白水解依赖性途径的RNA干扰稳定下调PSAP，降低β 1A-整合素表达、其细胞表面聚集和与基底膜蛋白的粘附;导致粘着斑复合物的分解;并降低粘着斑激酶及其下游衔接分子桩蛋白的磷酸化活性。组织蛋白酶D（CathD）的表达和蛋白水解活性，迁移和侵袭也显着降低PSAP敲低细胞。β1A整合素或CathD-siRNA寡核苷酸瞬时转染研究证实了PSAP和CathD或PSAP和Cer-β1A整合素之间的因果关系，调节PCa细胞的迁移和侵袭。PSAP通过协同调节Cer水平、CathD和β 1A-整合素的表达，减弱整合素信号通路的“由内而外”，参与PCa的侵袭，因此PSAP有可能成为PCa治疗的分子靶点。
Factors responsible for invasive and metastatic progression of prostate cancer (PCa) remain largely unknown. Previously, we reported cloning of prosaposin (PSAP) and its genomic amplification and/or overexpression in several androgen-independent metastatic PCa cell lines and lymph node metastases. PSAP is the lysosomal precursor of saposins, which serve as activators for lysosomal hydrolases involved in the degradation of ceramide (Cer) and other sphingolipids. Our current data show that, in metastatic PCa cells, stable down-modulation of PSAP by RNA-interference via a lysosomal proteolysis-dependent pathway decreased β1A-integrin expression, its cell-surface clustering, and adhesion to basement membrane proteins; led to disassembly of focal adhesion complex; and decreased phosphorylative activity of focal adhesion kinase and its downstream adaptor molecule, paxillin. Cathepsin D (CathD) expression and proteolytic activity, migration, and invasion were also significantly decreased in PSAP knock-down cells. Transient-transfection studies with β1A integrin- or CathD-siRNA oligos confirmed the cause and effect relationship between PSAP and CathD or PSAP and Cer-β1A integrin, regulating PCa cell migration and invasion. Our findings suggest that by a coordinated regulation of Cer levels, CathD and β1A-integrin expression, and attenuation of "inside-out" integrin-signaling pathway, PSAP is involved in PCa invasion and therefore might be used as a molecular target for PCa therapy.
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影响因子：
4.4
作者：
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10.1016/s0006-291x(05)80141-x
发表时间：
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影响因子：
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作者：
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通讯作者：
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