Momordin Ic, a new natural SENP1 inhibitor, inhibits prostate cancer cell proliferation.
Momordin Ic, a new natural SENP1 inhibitor, inhibits prostate cancer cell proliferation.
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Momordin Ic 是一种新型天然 SENP1 抑制剂，可抑制前列腺癌细胞增殖。
DOI：
10.18632/oncotarget.10636
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发表时间：
2016-09-13
期刊：
影响因子：
--
通讯作者：
Wu Y
中科院分区：
文献类型：
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作者：
Wu J;Lei H;Zhang J;Chen X;Tang C;Wang W;Xu H;Xiao W;Gu W;Wu Y
SUMO 特异性蛋白酶 1 (SENP1) 是去 SUMO 化蛋白酶家族的成员，在前列腺癌 (PCa) 细胞中表达升高，并参与 PCa 发病机制。苦瓜苷 Ic (Mc) 是一种天然五环三萜类化合物，在体外抑制 SENP1，如 SENP1C 诱导的 SUMO2-ΔRanGAP1 裂解减少所反映。 Mc 还在新开发的细胞热位移测定中改变了 SENP1 的热稳定性，表明 Mc 直接与 PCa 细胞中的 SENP1 相互作用。与 SENP1 抑制一致，Mc 增加了 SUMO 化蛋白水平，这通过 PC3 细胞中两种已知的 SUMO 化蛋白、缺氧诱导因子 1a 和伏隔核相关蛋白 1 的积累进一步证实。与LNCaP和正常前列腺上皮RWPE-1细胞相比，PC3细胞具有更高水平的SENP1 mRNA，并且对Mc诱导的生长抑制更敏感。 Mc 还降低了 PCa 细胞中 SENP1 mRNA 的水平。 SENP1 的过度表达可将 PC3 细胞从 Mc 诱导的细胞凋亡中拯救出来。最后，Mc 在异种移植 PC3 肿瘤小鼠模型中抑制细胞增殖并诱导体内细胞死亡。这些发现表明 Mc 是一种新型 SENP1 抑制剂，对 PCa 具有潜在的治疗价值。对其他五环三萜类化合物的研究可能有助于新型 SENP1 抑制剂药物的开发。
SUMO-specific protease 1 (SENP1), a member of the de-SUMOylation protease family, is elevated in prostate cancer (PCa) cells and is involved in PCa pathogenesis. Momordin Ιc (Mc), a natural pentacyclic triterpenoid, inhibited SENP1 in vitro, as reflected by reduced SENP1C-induced cleavage of SUMO2-ΔRanGAP1. Mc also altered the thermal stability of SENP1 in a newly developed cellular thermal shift assay, indicating that Mc directly interacts with SENP1 in PCa cells. Consistent with SENP1 inhibition, Mc increased SUMOylated protein levels, which was further confirmed by the accumulation of two known SUMOylated proteins, hypoxia inducible factor-1a and nucleus accumbens associated protein 1 in PC3 cells. Compared to LNCaP and normal prostate epithelial RWPE-1 cells, PC3 cells had higher levels of SENP1 mRNA and were more sensitive to Mc-induced growth inhibition. Mc also reduced SENP1 mRNA levels in PCa cells. Overexpression of SENP1 rescued PC3 cells from Mc-induced apoptosis. Finally, Mc suppressed cell proliferation and induced cell death in vivo in a xenograft PC3 tumor mouse model. These findings demonstrate that Mc is a novel SENP1 inhibitor with potential therapeutic value for PCa. Investigation of other pentacyclic triterpenoids may aid in the development of novel SENP1 inhibitor drugs.