VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2.
VNLG-152R and its deuterated analogs potently inhibit/repress triple/quadruple negative breast cancer of diverse racial origins in vitro and in vivo by upregulating E3 Ligase Synoviolin 1 (SYVN1) and inducing proteasomal degradation of MNK1/2.
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DOI：
10.3389/fonc.2023.1240996
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发表时间：
2023
影响因子：
4.7
通讯作者：
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三阴性乳腺癌（TNBC）及其近期发现的亚型四阴性乳腺癌（QNBC）在美国报告的乳腺癌病例中总计约占13%。这些侵袭性的乳腺癌类型预后不良，治疗选择有限，总体生存率较低。在先前的研究中，我们的研究表明VNLG - 152R在体外和体内对三阴性乳腺癌细胞均表现出抑制作用，并且氘代类似物在体外是对三阴性乳腺癌细胞更有效的抑制剂。基于这些发现，我们当前的研究深入探究了这种抑制作用背后的分子机制。通过转录组和蛋白质组分析，我们发现VNLG - 152R上调了三阴性乳腺癌细胞中E3连接酶滑膜素1（SYVN1）的表达，SYVN1也被称为3 - 羟基 - 3 - 甲基戊二酰还原酶降解蛋白（HRD1）。此外，我们提供了遗传学和药理学证据来证明SYVN1介导了MNK1/2的泛素化以及随后的蛋白酶体降解，MNK1/2是已知的唯一负责使eIF4E磷酸化的激酶。eIF4E的磷酸化是eIF4F翻译起始复合物形成的一个限速步骤，VNLG - 152R及其类似物对MNK1/2的降解阻碍了三阴性乳腺癌细胞中失调的翻译，从而抑制了肿瘤生长。重要的是，我们的发现在体内使用源自MDA - MB - 231、MDA - MB - 468和MDA - MB - 453细胞系的三阴性乳腺癌异种移植模型得到了验证，这些细胞系代表了不同的种族起源和遗传背景。这些异种移植模型涵盖了具有不同雄激素受体（AR）表达水平的三阴性乳腺癌，在NRG小鼠中通过口服VNLG - 152R及其氘代类似物可有效地抑制肿瘤。重要的是，在直接比较中，我们的化合物在抑制小鼠AR + MDA - MD - 453异种移植模型中的肿瘤生长方面比恩杂鲁胺和多西他赛更有效。总之，我们的研究揭示了SYVN1 E3连接酶在VNLG - 152R诱导的MNK1/2降解中的作用，以及VNLG - 152R及其更有效的氘代类似物作为治疗不同患者群体的三阴性乳腺癌的有前景的药物的治疗潜力。
Triple-negative breast cancer (TNBC) and its recently identified subtype, quadruple negative breast cancer (QNBC), collectively account for approximately 13% of reported breast cancer cases in the United States. These aggressive forms of breast cancer are associated with poor prognoses, limited treatment options, and lower overall survival rates. In previous studies, our research demonstrated that VNLG-152R exhibits inhibitory effects on TNBC cells both in vitro and in vivo and the deuterated analogs were more potent inhibitors of TNBC cells in vitro. Building upon these findings, our current study delves into the molecular mechanisms underlying this inhibitory action. Through transcriptome and proteome analyses, we discovered that VNLG-152R upregulates the expression of E3 ligase Synoviolin 1 (SYVN1), also called 3-hydroxy-3-methylglutaryl reductase degradation (HRD1) in TNBC cells. Moreover, we provide genetic and pharmacological evidence to demonstrate that SYVN1 mediates the ubiquitination and subsequent proteasomal degradation of MNK1/2, the only known kinases responsible for phosphorylating eIF4E. Phosphorylation of eIF4E being a rate-limiting step in the formation of the eIF4F translation initiation complex, the degradation of MNK1/2 by VNLG-152R and its analogs impedes dysregulated translation in TNBC cells, resulting in the inhibition of tumor growth. Importantly, our findings were validated in vivo using TNBC xenograft models derived from MDA-MB-231, MDA-MB-468, and MDA-MB-453 cell lines, representing different racial origins and genetic backgrounds. These xenograft models, which encompass TNBCs with varying androgen receptor (AR) expression levels, were effectively inhibited by oral administration of VNLG-152R and its deuterated analogs in NRG mice. Importantly, in direct comparison, our compounds are more effective than enzalutamide and docetaxel in achieving tumor growth inhibition/repression in the AR+ MDA-MD-453 xenograft model in mice. Collectively, our study sheds light on the involvement of SYVN1 E3 ligase in the VNLG-152R-induced degradation of MNK1/2 and the therapeutic potential of VNLG-152R and its more potent deuterated analogs as promising agents for the treatment of TNBC across diverse patient populations.
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整合蛋白质组学揭示了E3泛素连接酶Syvn1在肝细胞癌转移中的作用。
DOI：
10.1002/cac2.12192
发表时间：
2021-10
期刊：
Cancer communications (London, England)
影响因子：
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作者：
Ji F;Zhou M;Sun Z;Jiang Z;Zhu H;Xie Z;Ouyang X;Zhang L;Li L
通讯作者：
Li L
影响因子：
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作者：
Jiang HS;Kuang XY;Sun WL;Xu Y;Zheng YZ;Liu YR;Lang GT;Qiao F;Hu X;Shao ZM
通讯作者：
Shao ZM
DOI：
10.1186/s13058-020-01369-5
发表时间：
2020-11-19
期刊：
Breast cancer research : BCR
影响因子：
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作者：
Bhattarai S;Saini G;Gogineni K;Aneja R
通讯作者：
Aneja R
影响因子：
--
作者：
Hung JY;Yen MC;Jian SF;Wu CY;Chang WA;Liu KT;Hsu YL;Chong IW;Kuo PL
通讯作者：
Kuo PL
影响因子：
5.7
作者：
通讯作者：
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