PDF(Pubmed)
Abstract：
Bladder cancer aggressiveness is correlated with abnormal N-cadherin transmembrane glycoprotein expression. This protein is cleaved by the metalloprotease ADAM10 and the γ-secretase complex releasing a pro-angiogenic N-terminal fragment (NTF) and a proliferation-activating soluble C-terminal fragment (CTF2). Tetraspanin 15 (Tspan15) is identified as an ADAM10-interacting protein to induce selective N-cadherin cleavage. We first demonstrated, in invasive T24 bladder cancer cells, that N-cadherin was cleaved by ADAM10 generating NTF in the extracellular environment and leaving a membrane-anchored CTF1 fragment and that Tspan15 is required for ADAM10 to induce the selective N-cadherin cleavage. Targeting N-cadherin function in cancer is relevant to preventing tumor progression and metastases. For antitumor molecules to inhibit N-cadherin function, they should be complete and not cleaved. We first showed that the GW501516, an agonist of the nuclear receptor PPARβ/δ, decreased Tspan15 and prevented N-cadherin cleavage thus decreasing NTF. Interestingly, the drug did not modify ADAM10 expression, which was important because it could limit side effects since ADAM10 cleaves numerous substrates. By targeting Tspan15 to block ADAM10 activity on N-cadherin, GW501516 could prevent NTF pro-tumoral effects and be a promising molecule to treat bladder cancer. More interestingly, it could optimize the effects of the N-cadherin antagonists those such as ADH-1 that target the N-cadherin ectodomain.
摘要：
膀胱癌侵袭性与N-钙粘蛋白跨膜糖蛋白表达异常相关。该蛋白质被金属蛋白酶ADAM10和γ-分泌酶复合物裂解，释放促血管生成N末端片段（NTF）和增殖激活性可溶性C末端片段（CTF2）。Tetraspanin15（Tspan15）被鉴定为ADAM10相互作用蛋白，可诱导选择性N-钙粘蛋白裂解。我们首先证明，在侵袭性T24膀胱癌细胞中，N-cadherin被ADAM10裂解，在细胞外环境中产生NTF并留下膜锚定的CTF1片段，并且Tspan15是ADAM10诱导选择性N-cadherin裂解所必需的。在癌症中靶向N-钙黏着蛋白功能与预防肿瘤进展和转移有关。对于抑制N-钙粘蛋白功能的抗肿瘤分子，它们应该是完整的，而不是分裂的。我们首先表明GW501516，核受体PPARβ/δ的激动剂，降低Tspan15并防止N-钙黏着蛋白裂解，从而降低NTF。有趣的是,该药物没有改变ADAM10的表达，这是重要的，因为它可以限制副作用，因为ADAM10切割许多底物。通过靶向Tspan15来阻断ADAM10对N-钙粘蛋白的活性，GW501516可以预防NTF肿瘤前效应，是治疗膀胱癌的有前途的分子。更有趣的是，它可以优化N-cadherin拮抗剂的作用，例如靶向N-cadherin胞外域的ADH-1。
