Wünsch D, Hahlbrock A, Jung S, Schirmeister T, van den Boom J, Schilling O, Knauer S K, Stauber R H
Molecular and Cellular Oncology, ENT/University Medical Center of Mainz, Mainz, Germany.
Institute for Pharmacy and Biochemistry, University of Mainz, Mainz, Germany.
Oncogene. 2016 Jun 30;35(26):3351-64. doi: 10.1038/onc.2015.436. Epub 2015 Dec 14.
Proteolysis is not only a critical requirement for life, but the executing enzymes also play important roles in numerous pathological conditions, including cancer. Therefore, targeting proteases is clearly relevant for improving cancer patient care. However, to effectively control proteases, a profound knowledge of their mechanistic function as well as their regulation and downstream signalling in health and disease is required. The highly conserved protease Threonine Aspartase1 (Taspase1) is overexpressed in numerous liquid and solid malignancies and was characterized as a 'non-oncogene addiction' protease. Although Taspase1 was shown to cleave various regulatory proteins in humans as well as leukaemia provoking mixed lineage leukaemia fusions, our knowledge on its detailed functions and the underlying mechanisms contributing to cancer is still incomplete. Despite superficial similarity to type 2 asparaginases as well as Ntn proteases, such as the proteasome, Taspase1-related research so far gives us the picture of a unique protease exhibiting special features. Moreover, neither effective genetic nor chemical inhibitors for this enzyme are available so far, thus hampering not only to further dissect Taspase1's pathobiological functions but also precluding the assessment of its clinical impact. Based on recent insights, we here critically review the current knowledge of Taspase1's structure-function relationship and its mechanistic relevance for tumorigenesis obtained from in vitro and in vivo cancer models. We provide a comprehensive overview of tumour entities for which Taspase1 might be of predictive and therapeutic value, and present the respective experimental evidence. To stimulate progress in the field, a comprehensive overview of Taspase1 targeting approaches is presented, including coverage of Taspase1-related patents. We conclude by discussing future inhibition strategies and relevant challenges, which need to be resolved by the field.
蛋白水解不仅是生命的一项关键需求，而且执行蛋白水解的酶在包括癌症在内的众多病理状况中也发挥着重要作用。因此，靶向蛋白酶显然与改善癌症患者的治疗密切相关。然而，要有效控制蛋白酶，就需要深入了解它们在健康和疾病状态下的机制功能、调控以及下游信号传导。高度保守的蛋白酶苏氨酸天冬氨酸酶1（Taspase1）在多种血液和实体恶性肿瘤中过度表达，并被表征为一种“非癌基因成瘾”蛋白酶。尽管已表明Taspase1可切割人类中的各种调节蛋白以及引发白血病的混合谱系白血病融合蛋白，但我们对其详细功能以及导致癌症的潜在机制的了解仍然不完整。尽管Taspase1与2型天冬酰胺酶以及Ntn蛋白酶（如蛋白酶体）表面相似，但迄今为止，与Taspase1相关的研究让我们看到了一种具有特殊特征的独特蛋白酶。此外，到目前为止，还没有针对该酶的有效基因抑制剂或化学抑制剂，这不仅阻碍了进一步剖析Taspase1的病理生物学功能，也排除了对其临床影响的评估。基于最近的见解，我们在此批判性地回顾了目前关于Taspase1结构-功能关系及其从体外和体内癌症模型中获得的对肿瘤发生的机制相关性的认识。我们全面概述了Taspase1可能具有预测和治疗价值的肿瘤实体，并展示了相应的实验证据。为了推动该领域的进展，我们给出了Taspase1靶向方法的全面概述，包括对与Taspase1相关专利的介绍。我们通过讨论未来的抑制策略和相关挑战来得出结论，这些挑战需要该领域来解决。
