Lai Jinping, Chien Jeremy, Staub Julie, Avula Rajeswari, Greene Eddie L, Matthews Tori A, Smith David I, Kaufmann Scott H, Roberts Lewis R, Shridhar Viji
Mayo Clinic Cancer Center, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
J Biol Chem. 2003 Jun 20;278(25):23107-17. doi: 10.1074/jbc.M302203200. Epub 2003 Apr 9.
Emerging data suggest that signaling by heparin-binding growth factors is influenced by the sulfation state of N-acetylglucosamine residues of heparan sulfate proteoglycans (HSPGs). Here we report that the recently identified protein HSulf-1, a heparin-degrading endosulfatase, encodes a cell surface-associated enzyme that diminishes sulfation of cell surface HSPGs. The message encoding this enzyme is readily detectable in a variety of normal tissues, including normal ovarian surface epithelial cells, but is undetectable in 5 of 7 ovarian carcinoma cell lines and markedly diminished or undetectable in approximately 75% of ovarian cancers. Similar down-regulation is also observed in breast, pancreatic, renal cells, and hepatocellular carcinoma lines. Re-expression of HSulf-1 in ovarian cancer cell lines resulted in diminished HSPG sulfation, diminished phosphorylation of receptor tyrosine kinases that require sulfated HSPGs as co-receptors for their cognate ligands, and diminished downstream signaling through the extracellular signal-regulated kinase pathway after treatment with fibroblast growth factor-2 or heparin-binding epidermal growth factor. Consistent with these changes, HSulf-1 re-expression resulted in reduced proliferation as well as sensitivity to induction of apoptosis by the broad spectrum kinase inhibitor staurosporine and the chemotherapeutic agent cisplatin. Collectively, these observations provide evidence that HSulf-1 modulates signaling by heparin-binding growth factors, and HSulf-1 down-regulation represents a novel mechanism by which cancer cells can enhance growth factor signaling.
新出现的数据表明，硫酸乙酰肝素蛋白聚糖（HSPGs）的N-乙酰葡糖胺残基的硫酸化状态会影响肝素结合生长因子的信号传导。在此我们报告，最近鉴定出的蛋白HSulf-1，一种肝素降解性内切硫酸酯酶，编码一种细胞表面相关酶，该酶可减少细胞表面HSPGs的硫酸化。编码这种酶的信息在包括正常卵巢表面上皮细胞在内的多种正常组织中很容易检测到，但在7种卵巢癌细胞系中的5种中无法检测到，并且在大约75%的卵巢癌中明显减少或无法检测到。在乳腺癌、胰腺、肾细胞和肝癌细胞系中也观察到类似的下调。HSulf-1在卵巢癌细胞系中的重新表达导致HSPG硫酸化减少，需要硫酸化HSPGs作为其同源配体的共受体的受体酪氨酸激酶的磷酸化减少，以及在用成纤维细胞生长因子-2或肝素结合表皮生长因子处理后通过细胞外信号调节激酶途径的下游信号传导减少。与这些变化一致，HSulf-1的重新表达导致增殖减少以及对广谱激酶抑制剂星形孢菌素和化疗药物顺铂诱导的细胞凋亡的敏感性降低。总的来说，这些观察结果提供了证据，表明HSulf-1调节肝素结合生长因子的信号传导，并且HSulf-1的下调代表了癌细胞增强生长因子信号传导的一种新机制。
