Department of Biochemistry , University of Toronto , Toronto , Ontario M5G 1M1 , Canada.
Department of Chemistry , University of Toronto , Toronto , Ontario M5S 3H6 , Canada.
ACS Chem Biol. 2019 Nov 15;14(11):2349-2360. doi: 10.1021/acschembio.9b00347. Epub 2019 Jul 10.
The human ClpP proteolytic complex (HsClpP) is a serine protease located in the mitochondrial matrix and participates in the maintenance of the mitochondrial proteome among other cellular functions. HsClpP typically forms a multimeric complex with the AAA+ protein unfoldase HsClpX. Notably, compared to that of normal, healthy cells, the expression of HsClpP in many types of solid and nonsolid cancers is found to be upregulated. While the exact role of HsClpP in tumorigenesis is not clear, certain types of cancers are highly dependent on the protease for cell proliferation and metastasis. In light of these observations, recent research has focused on the discovery and characterization of small organic molecules that can target and modulate HsClpP activity. These include compounds that inhibit HsClpP's proteolytic activity via covalent modification of its catalytic Ser residue as well as those that activate and dysregulate HsClpP by displacing HsClpX to negate its regulatory role. Importantly, several of these compounds have been shown to induce HsClpP-dependent apoptotic cell death in a variety of cancerous cells. This review provides an overview of these research efforts and highlights the various types of small molecule modulators of HsClpP activity with respect to their potential use as cancer therapeutics.
人源 ClpP 蛋白酶体复合物（HsClpP）是一种位于线粒体基质中的丝氨酸蛋白酶，参与维持线粒体蛋白质组以及其他细胞功能。HsClpP 通常与 AAA+蛋白解折叠酶 HsClpX 形成多聚体复合物。值得注意的是，与正常健康细胞相比，许多类型的实体瘤和非实体瘤中 HsClpP 的表达被发现上调。尽管 HsClpP 在肿瘤发生中的确切作用尚不清楚，但某些类型的癌症高度依赖蛋白酶进行细胞增殖和转移。鉴于这些观察结果，最近的研究集中在发现和表征可以靶向和调节 HsClpP 活性的小分子有机化合物上。这些化合物包括通过共价修饰其催化 Ser 残基来抑制 HsClpP 蛋白水解活性的化合物，以及通过置换 HsClpX 来激活和失调 HsClpP 从而否定其调节作用的化合物。重要的是，这些化合物中的几种已被证明可在多种癌细胞中诱导 HsClpP 依赖性凋亡性细胞死亡。本综述概述了这些研究进展，并强调了 HsClpP 活性的各种小分子调节剂的类型，以及它们作为癌症治疗剂的潜在用途。
