PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma
PTEN status determines chemosensitivity to proteasome inhibition in cholangiocarcinoma
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PTEN 状态决定胆管癌中蛋白酶体抑制的化学敏感性
DOI：
10.1126/scitranslmed.aay0152
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发表时间：
2020-09-23
影响因子：
17.1
通讯作者：
Wang, Hong-Yang
中科院分区：
文献类型：
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作者：
Jiang, Tian-Yi;Pan, Yu-Fei;Wang, Hong-Yang
患者来源的异种移植物（PDX）和PDX来源的细胞（PDC）可用于临床前研究。我们使用PDCs进行药物筛选试验，并确定蛋白酶体抑制剂作为胆管癌（CCA）治疗的有前途的药物。此外，我们确定，磷酸盐和张力蛋白同源性缺失的10号染色体（PTEN）缺陷促进蛋白质合成和蛋白酶体亚单位的表达和蛋白水解活性，建立依赖于蛋白酶体癌细胞的生长和生存。因此，用抑制剂硼替佐米靶向蛋白酶体机制抑制了缺乏功能性PTEN的CCA细胞的增殖和存活。PDX、本地小鼠模型和患者的治疗评价证实了这种对蛋白酶体的依赖性。从机制上讲，我们发现PTEN促进FOXO 1的核转位，导致BACH 1和MAFF的表达增加。BACH 1和MAFF是识别抗氧化反应元件的转录调节因子，该元件存在于编码蛋白酶体亚基的基因中。PTEN可诱导这些蛋白的积累和核转位，从而直接抑制蛋白酶体亚基编码基因的转录。我们发现，PTEN-蛋白酶体轴是一个潜在的靶点，用于治疗PTEN缺陷型CCA和其他PTEN缺陷型癌症。
Patient-derived xenografts (PDXs) and PDX-derived cells (PDCs) are useful in preclinical research. We performed a drug screening assay using PDCs and identified proteasome inhibitors as promising drugs for cholangiocarcinoma (CCA) treatment. Furthermore, we determined that phosphate and tensin homology deleted on chromosome ten (PTEN) deficiency promotes protein synthesis and proteasome subunit expression and proteolytic activity, creating a dependency on the proteasome for cancer cell growth and survival. Thus, targeting the proteasome machinery with the inhibitor bortezomib inhibited the proliferation and survival of CCA cells lacking functional PTEN. Therapeutic evaluation of PDXs, autochthonous mouse models, and patients confirmed this dependency on the proteasome. Mechanistically, we found that PTEN promoted the nuclear translocation of FOXO1, resulting in the increased expression of BACH1 and MAFF. BACH1 and MAFF are transcriptional regulators that recognize the antioxidant response element, which is present in genes encoding proteasome subunits. PTEN induced the accumulation and nuclear translocation of these proteins, which directly repressed the transcription of genes encoding proteasome subunits. We revealed that the PTEN-proteasome axis is a potential target for therapy in PTEN-deficient CCA and other PTEN-deficient cancers.