DBT-AIST International Laboratory for Advanced Biomedicine [DAILAB], DAICENTER, National Institute of Advanced Industrial Science and Technology [AIST], Central 5-41, Higashi 1-1-1, Tsukuba, Ibaraki, 305 8565, Japan.
DAILAB, Department of Biochemical Engineering and Biotechnology, Indian Institute of Technology [IIT] Delhi, New Delhi, Hauz Khas, 110 016, India.
J Exp Clin Cancer Res. 2019 Dec 19;38(1):499. doi: 10.1186/s13046-019-1500-9.
Mortalin is enriched in a large variety of cancers and has been shown to contribute to proliferation and migration of cancer cells in multiple ways. It has been shown to bind to p53 protein in cell cytoplasm and nucleus causing inactivation of its tumor suppressor activity in cancer cells. Several other activities of mortalin including mitochondrial biogenesis, ATP production, chaperoning, anti-apoptosis contribute to pro-proliferative and migration characteristics of cancer cells. Mortalin-compromised cancer cells have been shown to undergo apoptosis in in vitro and in vivo implying that it could be a potential target for cancer therapy.
We implemented a screening of a chemical library for compounds with potential to abrogate cancer cell specific mortalin-p53 interactions, and identified a new compound (named it as Mortaparib) that caused nuclear enrichment of p53 and shift in mortalin from perinuclear (typical of cancer cells) to pancytoplasmic (typical of normal cells). Biochemical and molecular assays were used to demonstrate the effect of Mortaparib on mortalin, p53 and PARP1 activities.
Molecular homology search revealed that Mortaparib is a novel compound that showed strong cytotoxicity to ovarian, cervical and breast cancer cells. Bioinformatics analysis revealed that although Mortaparib could interact with mortalin, its binding with p53 interaction site was not stable. Instead, it caused transcriptional repression of mortalin leading to activation of p53 and growth arrest/apoptosis of cancer cells. By extensive computational and experimental analyses, we demonstrate that Mortaparib is a dual inhibitor of mortalin and PARP1. It targets mortalin, PARP1 and mortalin-PARP1 interactions leading to inactivation of PARP1 that triggers growth arrest/apoptosis signaling. Consistent with the role of mortalin and PARP1 in cancer cell migration, metastasis and angiogenesis, Mortaparib-treated cells showed inhibition of these phenotypes. In vivo tumor suppression assays showed that Mortaparib is a potent tumor suppressor small molecule and awaits clinical trials.
These findings report (i) the discovery of Mortaparib as a first dual inhibitor of mortalin and PARP1 (both frequently enriched in cancers), (ii) its molecular mechanism of action, and (iii) in vitro and in vivo tumor suppressor activity that emphasize its potential as an anticancer drug.
线粒体蛋白在多种癌症中含量丰富，并已被证实可通过多种方式促进癌细胞的增殖和迁移。它已被证明可与细胞质和细胞核中的 p53 蛋白结合，导致癌细胞中 p53 肿瘤抑制活性失活。线粒体蛋白的其他几种活性，包括线粒体生物发生、ATP 产生、伴侣蛋白、抗细胞凋亡，有助于癌细胞的促增殖和迁移特征。已证实，线粒体蛋白受损的癌细胞在体外和体内会发生细胞凋亡，这表明它可能是癌症治疗的潜在靶点。
我们对化学文库进行了筛选，寻找具有破坏癌细胞特异性线粒体蛋白-p53 相互作用潜力的化合物，并鉴定出一种新的化合物（命名为 Mortaparib），它导致 p53 核内富集，并使线粒体蛋白从核周（典型的癌细胞）转移到全细胞质（典型的正常细胞）。生化和分子测定用于证明 Mortaparib 对线粒体蛋白、p53 和 PARP1 活性的影响。
分子同源性搜索显示，Mortaparib 是一种新型化合物，对卵巢癌、宫颈癌和乳腺癌细胞具有很强的细胞毒性。生物信息学分析显示，虽然 Mortaparib 可以与线粒体蛋白相互作用，但它与 p53 相互作用位点的结合并不稳定。相反，它导致线粒体蛋白转录抑制，从而激活 p53 并导致癌细胞生长停滞/凋亡。通过广泛的计算和实验分析，我们证明 Mortaparib 是线粒体蛋白和 PARP1 的双重抑制剂。它靶向线粒体蛋白、PARP1 和线粒体蛋白-PARP1 相互作用，导致 PARP1 失活，触发生长停滞/凋亡信号。与线粒体蛋白和 PARP1 在癌细胞迁移、转移和血管生成中的作用一致，Mortaparib 处理的细胞表现出这些表型的抑制。体内肿瘤抑制实验表明，Mortaparib 是一种有效的肿瘤抑制小分子，有待临床试验。
这些发现报告了（i）Mortaparib 作为第一个线粒体蛋白和 PARP1 的双重抑制剂（两者在癌症中经常富集）的发现，（ii）其作用机制，以及（iii）体外和体内的肿瘤抑制活性，强调了其作为抗癌药物的潜力。
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