The synthetic oleanane triterpenoid CDDO-2P-Im binds GRP78/BiP to induce unfolded protein response-mediated apoptosis in myeloma.
The synthetic oleanane triterpenoid CDDO-2P-Im binds GRP78/BiP to induce unfolded protein response-mediated apoptosis in myeloma.
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DOI：
10.1002/1878-0261.13447
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发表时间：
2023-12
影响因子：
6.6
通讯作者：
Letterio, John J.
中科院分区：
文献类型：
--
作者：
Luo, George;Aldridge, Kristin;Chen, Toby;Aslot, Vivek;Kim, Byung-Gyu;Han, Eun Hyang;Singh, Neelima;Li, Sai;Xiao, Tsan Sam;Sporn, Michael B.;Letterio, John J.
合成齐墩烷三萜（SOTs）是具有广泛抗癌特性的小分子化合物。最近开发的SOT， 1‐[2‐氰基‐3,12‐二氧齐烷‐1,9（11）‐二烯‐28‐油基]‐4（‐吡啶‐2‐基）‐1H‐咪唑（CDDO‐2P‐Im或‘ 2P‐Im ’），与上一代SOT CDDO‐Im相比，具有更强的活性和更好的药代动力学。但是，没有定义导致这些属性的机制。在这里，我们展示了2P‐Im和蛋白酶体抑制剂ixazomib在人多发性骨髓瘤（MM）细胞中的协同作用，以及2P‐Im在小鼠浆细胞瘤模型中的活性。RNA测序和定量反转录PCR显示，2P‐lm处理后MM细胞的未折叠蛋白反应（UPR）上调，暗示UPR的激活是2P‐lm诱导细胞凋亡的关键步骤。为了支持这一假设，缺失编码蛋白激酶R样内质网激酶（PERK）或DNA损伤诱导转录物3蛋白（DDIT3，也称为CHOP）的基因会损害MM对2P‐Im的反应，与ISRIB治疗一样，ISRIB是一种综合应激反应抑制剂，可抑制PERK下游的UPR信号传导。最后，药物亲和反应靶稳定性和热移试验均表明2P‐Im与内质网伴侣BiP （GRP78/BiP）直接结合，后者是一种应激诱导的UPR关键信号分子。这些数据表明GRP78/BiP是sot的新靶点，特别是2P‐Im，并表明这类小分子作为UPR调节剂的潜在更广泛的用途。合成的齐墩烷三萜CDDO‐2P‐Im以浓度依赖的方式选择性地与特定蛋白靶点相互作用。在低浓度下，它与KEAP1结合导致Nrf2靶基因表达的激活。随着CDDO‐2P‐Im浓度的增加，它与GRP78结合，导致未折叠蛋白反应的激活和ATF4和XBP1靶基因的上调。
Synthetic oleanane triterpenoids (SOTs) are small molecules with broad anticancer properties. A recently developed SOT, 1‐[2‐cyano‐3,12‐dioxooleana‐1,9(11)‐dien‐28‐oyl]‐4(‐pyridin‐2‐yl)‐1H‐imidazole (CDDO‐2P‐Im or ‘2P‐Im’), exhibits enhanced activity and improved pharmacokinetics over CDDO‐Im, a previous generation SOT. However, the mechanisms leading to these properties are not defined. Here, we show the synergy of 2P‐Im and the proteasome inhibitor ixazomib in human multiple myeloma (MM) cells and 2P‐Im activity in a murine model of plasmacytoma. RNA sequencing and quantitative reverse transcription PCR revealed the upregulation of the unfolded protein response (UPR) in MM cells upon 2P‐lm treatment, implicating the activation of the UPR as a key step in 2P‐Im‐induced apoptosis. Supporting this hypothesis, the deletion of genes encoding either protein kinase R‐like endoplasmic reticulum kinase (PERK) or DNA damage‐inducible transcript 3 protein (DDIT3; also known as CHOP) impaired the MM response to 2P‐Im, as did treatment with ISRIB, integrated stress response inhibitor, which inhibits UPR signaling downstream of PERK. Finally, both drug affinity responsive target stability and thermal shift assays demonstrated direct binding of 2P‐Im to endoplasmic reticulum chaperone BiP (GRP78/BiP), a stress‐inducible key signaling molecule of the UPR. These data reveal GRP78/BiP as a novel target of SOTs, and specifically of 2P‐Im, and suggest the potential broader utility of this class of small molecules as modulators of the UPR. The synthetic oleanane triterpenoid CDDO‐2P‐Im selectively interacts with specific protein targets in a concentration‐dependent manner. At low concentrations, its binding to KEAP1 leads to the activation of Nrf2 target gene expression. As the concentration of CDDO‐2P‐Im increases, it binds to GRP78, leading to the activation of the unfolded protein response and the upregulation of ATF4 and XBP1 target genes.
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影响因子：
14.9
作者：
Chorley BN;Campbell MR;Wang X;Karaca M;Sambandan D;Bangura F;Xue P;Pi J;Kleeberger SR;Bell DA
通讯作者：
Bell DA
影响因子：
3.7
作者：
Singh, Navneet;Romick-Rosendale, Lindsey;Watanabe-Chailland, Miki;Privette Vinnedge, Lisa M;Komurov, Kakajan
通讯作者：
Komurov, Kakajan
影响因子：
4.7
作者：
通讯作者：
--
影响因子：
4.3
作者：
Casas C
通讯作者：
Casas C
影响因子：
11.2
作者：
Ahmad, Rehan;Raina, Deepak;Kufe, Donald
通讯作者：
Kufe, Donald