Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.
Targeting proliferating cell nuclear antigen and its protein interactions induces apoptosis in multiple myeloma cells.
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DOI：
10.1371/journal.pone.0070430
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Otterlei M
中科院分区：
文献类型：
--
作者：
Müller R;Misund K;Holien T;Bachke S;Gilljam KM;Våtsveen TK;Rø TB;Bellacchio E;Sundan A;Otterlei M
多发性骨髓瘤是一种血液癌症，尽管过去十年治疗策略取得了进展，但仍被认为无法治愈。由于恶性肿瘤的异质性，针对单一途径的治疗不太可能成功。增殖细胞核抗原 (PCNA) 是 DNA 复制和修复所必需的多功能蛋白质，通常在癌细胞中过度表达。许多参与细胞应激反应的蛋白质通过五个氨基酸序列 AlkB 同源物 2 PCNA 相互作用基序 (APIM) 与 PCNA 相互作用。因此，抑制 PCNA 的蛋白质相互作用可能是同时靶向多个途径的好策略。我们最初发现含有 APIM 序列的肽的过度表达会增加癌细胞对当代疗法的敏感性。在这里，我们设计了一种含有 APIM 的细胞穿透肽 ATX-101，它靶向 PCNA，并显示其具有抗骨髓瘤活性。我们发现 ATX-101 诱导多发性骨髓瘤细胞系和原代癌细胞凋亡，而骨髓基质细胞和原代健康淋巴细胞的敏感性要低得多。 ATX-101 诱导的细胞凋亡是半胱天冬酶依赖性的且与细胞周期阶段无关。 ATX-101 还增加了多发性骨髓瘤细胞对美法仑（一种常用于治疗多发性骨髓瘤的 DNA 损伤剂）的敏感性。在异种移植小鼠模型中，ATX-101 具有良好的耐受性并增强了美法仑的抗肿瘤活性。因此，ATX-101靶向PCNA可能是多发性骨髓瘤治疗的新策略。
Multiple myeloma is a hematological cancer that is considered incurable despite advances in treatment strategy during the last decade. Therapies targeting single pathways are unlikely to succeed due to the heterogeneous nature of the malignancy. Proliferating cell nuclear antigen (PCNA) is a multifunctional protein essential for DNA replication and repair that is often overexpressed in cancer cells. Many proteins involved in the cellular stress response interact with PCNA through the five amino acid sequence AlkB homologue 2 PCNA-interacting motif (APIM). Thus inhibiting PCNA’s protein interactions may be a good strategy to target multiple pathways simultaneously. We initially found that overexpression of peptides containing the APIM sequence increases the sensitivity of cancer cells to contemporary therapeutics. Here we have designed a cell-penetrating APIM-containing peptide, ATX-101, that targets PCNA and show that it has anti-myeloma activity. We found that ATX-101 induced apoptosis in multiple myeloma cell lines and primary cancer cells, while bone marrow stromal cells and primary healthy lymphocytes were much less sensitive. ATX-101-induced apoptosis was caspase-dependent and cell cycle phase-independent. ATX-101 also increased multiple myeloma cells’ sensitivity against melphalan, a DNA damaging agent commonly used for treatment of multiple myeloma. In a xenograft mouse model, ATX-101 was well tolerated and increased the anti-tumor activity of melphalan. Therefore, targeting PCNA by ATX-101 may be a novel strategy in multiple myeloma treatment.
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