PDF(Pubmed)
Abstract：
The 78-kDa glucose regulated protein (GRP78) commonly upregulated in a wide variety of tumors is an important prognostic marker and a promising target for suppressing tumorigenesis and treatment resistance. While GRP78 is well established as a major endoplasmic reticulum (ER) chaperone with anti-apoptotic properties and a master regulator of the unfolded protein response, its new role as a regulator of oncoprotein expression is just emerging. MYC is dysregulated in about 70 % of human cancers and is the most commonly activated oncoprotein. However, despite recent advances, therapeutic targeting of MYC remains challenging. Here we identify GRP78 as a new target for suppression of MYC expression. Using multiple MYC-dependent cancer models including head and neck squamous cell carcinoma and their cisplatin-resistant clones, breast and pancreatic adenocarcinoma, our studies revealed that GRP78 knockdown by siRNA or inhibition of its activity by small molecule inhibitors (YUM70 or HA15) reduced c-MYC expression, leading to onset of apoptosis and loss of cell viability. This was observed in 2D cell culture, 3D spheroid and in xenograft models. Mechanistically, we determined that the suppression of c-MYC is at the post-transcriptional level and that YUM70 and HA15 treatment potently upregulated the eukaryotic translation inhibitor 4E-BP1, which targets eIF4E critical for c-MYC translation initiation. Furthermore, knock-down of 4E-BP1 via siRNA rescued YUM70-mediated c-MYC suppression. As YUM70 is also capable of suppressing N-MYC expression, this study offers a new approach to suppress MYC protein expression through knockdown or inhibition of GRP78.
摘要：
通常在多种肿瘤中上调的78kDa葡萄糖调节蛋白（GRP78）是重要的预后标志物，也是抑制肿瘤发生和治疗抗性的有希望的靶标。虽然GRP78已被公认为具有抗凋亡特性的主要内质网（ER）伴侣和未折叠蛋白反应的主要调节因子，它作为癌蛋白表达调节剂的新作用刚刚出现。MYC在约70％的人类癌症中失调，是最常见的活化癌蛋白。然而,尽管最近取得了进展，MYC的治疗靶向仍然具有挑战性.在这里，我们将GRP78确定为抑制MYC表达的新靶标。使用多种MYC依赖性癌症模型，包括头颈部鳞状细胞癌及其顺铂耐药克隆，乳腺和胰腺腺癌，我们的研究表明，通过siRNA敲低GRP78或通过小分子抑制剂（YUM70或HA15）抑制其活性降低c-MYC表达，导致细胞凋亡和细胞活力的丧失。这在2D细胞培养中观察到，3D球体和异种移植模型。机械上,我们确定c-MYC的抑制处于转录后水平,YUM70和HA15处理有效上调真核翻译抑制剂4E-BP1,其靶向对c-MYC翻译起始至关重要的eIF4E.此外，通过siRNA敲除4E-BP1拯救了YUM70介导的c-MYC抑制。由于YUM70还能够抑制N-MYC表达，这项研究提供了一种通过敲低或抑制GRP78来抑制MYC蛋白表达的新方法。
