The Natural Compound Oblongifolin C Exhibits Anticancer Activity by Inhibiting HSPA8 and Cathepsin B In Vitro.
The Natural Compound Oblongifolin C Exhibits Anticancer Activity by Inhibiting HSPA8 and Cathepsin B In Vitro.
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天然化合物 Oblongifolin C 通过在体外抑制 HSPA8 和组织蛋白酶 B 表现出抗癌活性。
DOI：
10.3389/fphar.2020.564833
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发表时间：
2020
影响因子：
5.6
通讯作者：
Xu H
中科院分区：
文献类型：
--
作者：
Han L;Xu D;Xi Z;Wu M;Nik Nabil WN;Zhang J;Sui H;Fu W;Zhou H;Lao Y;Xu G;Guo C;Xu H
PPAP（多环聚异戊二烯化酰基间苯三酚）是一类具有多种生物活性的化合物，包括抗癌作用。Oblongifolin C（OC）是从云南山竹（Garcinia yunnanensis Hu.）我们先前发现OC诱导癌细胞凋亡，抑制自噬流，并减弱癌细胞的转移。然而，OC的蛋白质靶点和详细的作用机制仍不清楚。为了鉴定OC的蛋白质靶点，进行了非标记蛋白质钓鱼测定，发现OC可以与几种蛋白质相互作用，包括热休克70 kDa蛋白8（HSPA8）。本研究在前人对组织蛋白酶B研究的基础上，应用表面等离子体共振（SPR）和等温滴定量热法（ITC）对OC与两种蛋白质靶点的结合亲和力进行了研究。本研究强调了OC对热休克应激下癌细胞中HSPA8的抑制作用，通过特异性抑制HSPA8的易位。OC还增强了HSPA8、HSP90和p53之间的相互作用，上调p53的表达，并显著促进顺铂处理的细胞的凋亡。此外，流式细胞仪检测发现，OC加快了HSPA8敲低的A549细胞的凋亡率，而HSPA8过表达延迟OC诱导的凋亡率。总之，我们的研究结果表明，OC可能与HSPA8和组织蛋白酶B相互作用，并抑制HSPA8核转位和组织蛋白酶B活性，这表明OC有潜力被开发为一种抗癌药物。
PPAPs (Polycyclic polyprenylated acylphloroglucinols) are a class of compounds with diverse bioactivities, including anticancer effects. Oblongifolin C (OC) is a PPAP isolated from the plant of Garcinia yunnanensis Hu. We previously discovered that OC induces apoptosis, inhibits autophagic flux, and attenuates metastasis in cancer cells. However, the protein targets and the detailed mechanism of action of OC remain unclear. To identify protein targets of OC, a non-labeled protein fishing assay was performed, and it was found that OC may interact with several proteins, including the heat shock 70 kDa protein 8 (HSPA8). Expanding on our previous studies on protein cathepsin B, this current study applied Surface Plasmon Resonance (SPR) and Isothermal Titration Calorimetry (ITC) to confirm the potential binding affinity between OC and two protein targets. This study highlights the inhibitory effect of OC on HSPA8 in cancer cells under heat shock stress, by specifically inhibiting the translocation of HSPA8. OC also enhanced the interaction between HSPA8, HSP90, and p53, upregulated the expression of p53 and significantly promoted apoptosis in cisplatin-treated cells. Additionally, a flow cytometry assay detected that OC sped up the apoptosis rate in HSPA8 knockdown A549 cells, while overexpression of HSPA8 delayed the OC-induced apoptosis rate. In summary, our results reveal that OC potentially interacts with HSPA8 and cathepsin B and inhibits HSPA8 nuclear translocation and cathepsin B activities, altogether suggesting the potential of OC to be developed as an anticancer drug.
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影响因子：
7.5
作者：
Hämälistö S;Jäättelä M
通讯作者：
Jäättelä M
DOI：
10.1002/prca.201300105
发表时间：
2014-06
期刊：
Proteomics. Clinical applications
影响因子：
--
作者：
Aggarwal N;Sloane BF
通讯作者：
Sloane BF
DOI：
10.1158/1541-7786.mcr-11-0019
发表时间：
2011-07
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Leu JI;Pimkina J;Pandey P;Murphy ME;George DL
通讯作者：
George DL
影响因子：
3.6
作者：
Budina-Kolomets, Anna;Balaburski, Gregor M.;Murphy, Maureen E.
通讯作者：
Murphy, Maureen E.
影响因子：
2.9
作者：
Andreotti G;Monticelli M;Cubellis MV
通讯作者：
Cubellis MV