Deficiency for the cysteine protease cathepsin L impairs Myc-induced tumorigenesis in a mouse model of pancreatic neuroendocrine cancer.
Deficiency for the cysteine protease cathepsin L impairs Myc-induced tumorigenesis in a mouse model of pancreatic neuroendocrine cancer.
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DOI：
10.1371/journal.pone.0120348
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Shchors K
中科院分区：
文献类型：
--
作者：
Brindle NR;Joyce JA;Rostker F;Lawlor ER;Swigart-Brown L;Evan G;Hanahan D;Shchors K
受最近半胱氨酸蛋白酶组织蛋白酶L作为抗癌药物开发的潜在靶点的影响，我们使用胰腺神经内分泌肿瘤发生（PNET）的条件性MycERTAM;Bcl-xL模型来评估组织蛋白酶L在Myc诱导的肿瘤进展中的作用。通过在体内和体外使用半胱氨酸组织蛋白酶活性探针，我们首先确定组织蛋白酶活性在MycERTAM;Bcl-xL肿瘤发展的初始阶段增加。在研究的组织蛋白酶家族成员中，只有组织蛋白酶L主要由胰腺肿瘤中的β-肿瘤细胞产生，并且与此一致，组织蛋白酶L mRNA表达在β细胞隔室中Myc激活后迅速上调。相比之下，组织蛋白酶B、S和C在肿瘤浸润性白细胞中高度富集。组织蛋白酶L的基因缺失对肿瘤生长或一致的血管生成的启动没有明显的影响。然而，在组织蛋白酶L缺陷背景中发展的肿瘤相对于其典型的野生型对应物在尺寸上显著减小，表明组织蛋白酶L在使肿瘤扩张生长中的作用。因此，组织蛋白酶L活性的遗传阻断被推断为延迟Myc驱动的肿瘤生长，鼓励半胱氨酸组织蛋白酶的药理学抑制剂在治疗晚期肿瘤中的潜在效用。
Motivated by the recent implication of cysteine protease cathepsin L as a potential target for anti-cancer drug development, we used a conditional MycERTAM;Bcl-xL model of pancreatic neuroendocrine tumorigenesis (PNET) to assess the role of cathepsin L in Myc-induced tumor progression. By employing a cysteine cathepsin activity probe in vivo and in vitro, we first established that cathepsin activity increases during the initial stages of MycERTAM;Bcl-xL tumor development. Among the cathepsin family members investigated, only cathepsin L was predominately produced by beta-tumor cells in neoplastic pancreata and, consistent with this, cathepsin L mRNA expression was rapidly upregulated following Myc activation in the beta cell compartment. By contrast, cathepsins B, S and C were highly enriched in tumor-infiltrating leukocytes. Genetic deletion of cathepsin L had no discernible effect on the initiation of neoplastic growth or concordant angiogenesis. However, the tumors that developed in the cathepsin L-deficient background were markedly reduced in size relative to their typical wild-type counterparts, indicative of a role for cathepsin L in enabling expansive tumor growth. Thus, genetic blockade of cathepsin L activity is inferred to retard Myc-driven tumor growth, encouraging the potential utility of pharmacological inhibitors of cysteine cathepsins in treating late stage tumors.
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