MCM2-7 complex is a novel druggable target for neuroendocrine prostate cancer.
MCM2-7 complex is a novel druggable target for neuroendocrine prostate cancer.
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DOI：
10.1038/s41598-021-92552-x
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发表时间：
2021-06-25
影响因子：
4.6
通讯作者：
Stoyanova T
中科院分区：
文献类型：
--
作者：
Hsu EC;Shen M;Aslan M;Liu S;Kumar M;Garcia-Marques F;Nguyen HM;Nolley R;Pitteri SJ;Corey E;Brooks JD;Stoyanova T
神经内分泌前列腺癌（NEPC）是前列腺癌的一种致死亚型，在原发性肿瘤中很少新发，通常在治疗耐药性的发展过程中获得。NEPC的特征在于神经内分泌标志物的获得和雄激素受体（AR）的丧失，使得其对靶向AR信号传导轴的当前治疗策略具有抗性。在这里，我们报告了MCM 2、MCM 3、MCM 4和MCM 6（MCM 2/3/4/6）在人NEPC中升高，并且高水平的MCM 2/3/4/6与前列腺癌患者的肝转移和较差的存活率相关。MCM 2/3/4/6是形成核心DNA解旋酶（MCM 2 -7）的六种蛋白中的四种，其负责在DNA复制期间解旋DNA叉。通过用环丙沙星处理来抑制MCM 2 -7在体外抑制NEPC细胞增殖和迁移，显著延迟NEPC肿瘤异种移植物生长，并且在体内部分逆转神经内分泌表型。我们的研究揭示了NEPC中MCM 2/3/4/6蛋白的临床相关性，并表明抑制MCM 2 -7可能代表NEPC的新治疗策略。
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 proteins in NEPC and suggests that inhibition of MCM2-7 may represent a new therapeutic strategy for NEPC.
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DOI：
10.1186/s13046-017-0669-z
发表时间：
2018-01-22
期刊：
Journal of experimental & clinical cancer research : CR
影响因子：
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影响因子：
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通讯作者：
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影响因子：
78.5
作者：
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影响因子：
5.2
作者：
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通讯作者：
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