Mechanistic Studies of the Multiple Myeloma and Melanoma Cell-Selective Toxicity of the Rpn13-Binding Peptoid KDT-11.
Mechanistic Studies of the Multiple Myeloma and Melanoma Cell-Selective Toxicity of the Rpn13-Binding Peptoid KDT-11.
复制标题
RPN13结合肽KDT-11的多发性骨髓瘤和黑色素瘤细胞选择性的机械研究。
DOI：
10.1016/j.chembiol.2020.08.008
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发表时间：
2020-11-19
影响因子：
8.6
通讯作者：
Kodadek T
中科院分区：
文献类型：
--
作者：
Dickson P;Simanski S;Ngundu JM;Kodadek T
我们先前报道了蛋白酶体泛素受体Rpn 13的类肽配体KDT-11，并证明该化合物对多发性骨髓瘤（MM）细胞有毒，但对非恶性细胞无毒。我们在这里表明，KDT-11降低了各种癌细胞系的活力，特别是黑色素瘤和各种血癌。类肽诱导选择性G1期细胞周期阻滞，最终导致细胞凋亡。虽然KDT-11不拮抗任何已知的涉及Rpn 13的蛋白质-蛋白质相互作用，但类肽抑制Rpn 13在体外刺激相关去泛素化酶Uch 37/UCHL 5活性的能力，表明高水平的Uch 37活性可能对癌细胞增殖很重要。然而，在SK-MEL-5黑色素瘤细胞中的各种实验表明，KDT-11的细胞毒性作用是通过与Rpn 13以外的蛋白质相互作用介导的。Dickson等人表征了肽模拟物KDT-11的作用机制，先前报道其结合Rpn 13并降低癌细胞的活力。通过生物化学和细胞方法，该小组证明KDT-11不会破坏Rpn 13已知的蛋白质相互作用，细胞对KDT-11的敏感性也与Rpn 13水平无关。
We previously reported a peptoid ligand for the proteasomal ubiquitin receptor Rpn13 called KDT-11 and demonstrated that this compound is toxic to multiple myeloma (MM) cells, but not non-malignant cells. We show here that KDT-11 decreases the viability of a variety of cancer cell lines, especially melanomas and various blood cancers. The peptoid induces selective G1 cell cycle arrest, resulting in eventual apoptosis. While KDT-11 does not antagonize any of the known protein-protein interactions involving Rpn13, the peptoid inhibits the ability of Rpn13 to stimulate the activity of an associated deubiquitylase Uch37/UCHL5 in vitro, suggesting a high level of Uch37 activity might be important for cancer cell proliferation. However, a variety of experiments in SK-MEL-5 melanoma cells suggest that KDT-11’s cytotoxic effects are mediated by interactions with proteins other than Rpn13. Dickson et al. characterize the mechanism of action of peptidomimetic KDT-11, previously reported to bind Rpn13 and reduce viability of cancer cells. Through biochemical and cellular approaches, the group demonstrates that KDT-11 does not disrupt Rpn13’s known protein interactions, nor is cellular sensitivity to KDT-11 correlated with Rpn13 levels.
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