A small-molecule drug inhibits autophagy gene expression through the central regulator TFEB.
A small-molecule drug inhibits autophagy gene expression through the central regulator TFEB.
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一种小分子药物通过中央调节因子TFEB抑制自噬基因的表达。
DOI：
10.1073/pnas.2213670120
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发表时间：
2023-02-14
影响因子：
11.1
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Lin Y;Shi Q;Yang G;Shi F;Zhou Y;Wang T;Xu P;Li P;Liu Z;Sun H;Zhao Z;Ding K;Wang Z;Feng H;Yu B;Fang P;Wang J
自噬是真核细胞中一种有序的降解机制。它通常在一系列人类疾病中失调，包括癌症。一些癌症依赖自噬来生存和发展。特别是，肿瘤细胞可以利用自噬来科普某些抗癌药物的细胞毒性。抑制自噬是肿瘤治疗的一个有前途的策略。然而，目前还没有有效的自噬抑制剂可用于临床。我们发现，靶向中央调节转录因子EB（TFEB）可以有效地抑制自噬在转录水平。我们发现美国食品和药物管理局（FDA）批准的药物艾曲泊帕实际上是一种针对TFEB的有效自噬抑制剂。这一发现可能有助于在临床实践中加速有效抑制自噬。自噬支持已建立的肿瘤的快速生长，并促进肿瘤对多种治疗的抗性。抑制自噬是肿瘤治疗的一个有前途的策略。然而，目前缺乏适合临床使用的有效自噬抑制剂。有一个高的需求，以确定新的自噬药物靶点和有效的抑制剂与药物一样的性质。转录因子EB（TFEB）是自噬的核心转录调节因子，其促进溶酶体的生物发生和功能，并系统地上调自噬。尽管有大量证据表明TFEB是一种有希望的自噬抑制靶点，但没有报道小分子TFEB抑制剂。在这里，我们发现美国食品药品监督管理局（FDA）批准的药物艾曲泊帕（EO）与TFEB的碱性螺旋-环-螺旋-亮氨酸拉链结构域结合，特别是螺旋-环-螺旋的底部表面与DNA识别发生冲突，并在体外和细胞环境中破坏TFEB-DNA相互作用。根据RNA测序分析，EO在基因组规模上选择性抑制TFEB的转录活性，以剂量依赖性方式阻断自噬，并增加胶质母细胞瘤对替莫唑胺的体内敏感性。总之，这项工作揭示了TFEB是可靶向的，并提出了第一个直接的TFEB抑制剂EO，这是一种具有很大潜力的药物化合物，通过抑制自噬使广泛的癌症治疗受益。
Autophagy is an orderly degradation mechanism in eukaryotic cells. It is often dysregulated in a range of human diseases, including cancer. Some cancers rely on autophagy to survive and develop. In particular, tumor cells can use autophagy to cope with the cytotoxicity of certain anticancer drugs. Inhibition of autophagy is a promising strategy for tumor therapy. However, there are currently no effective autophagy inhibitors available for clinical use. We show that targeting the central regulatory transcription factor EB (TFEB) can effectively inhibit autophagy at the transcriptional level. And we found that the United States Food and Drug Administration (FDA)-approved drug Eltrombopag is actually a potent autophagy inhibitor targeting TFEB. This finding may help accelerate effective inhibition of autophagy in clinical practice. Autophagy supports the fast growth of established tumors and promotes tumor resistance to multiple treatments. Inhibition of autophagy is a promising strategy for tumor therapy. However, effective autophagy inhibitors suitable for clinical use are currently lacking. There is a high demand for identifying novel autophagy drug targets and potent inhibitors with drug-like properties. The transcription factor EB (TFEB) is the central transcriptional regulator of autophagy, which promotes lysosomal biogenesis and functions and systematically up-regulates autophagy. Despite extensive evidence that TFEB is a promising target for autophagy inhibition, no small molecular TFEB inhibitors were reported. Here, we show that an United States Food and Drug Administration (FDA)-approved drug Eltrombopag (EO) binds to the basic helix-loop-helix-leucine zipper domain of TFEB, specifically the bottom surface of helix-loop-helix to clash with DNA recognition, and disrupts TFEB-DNA interaction in vitro and in cellular context. EO selectively inhibits TFEB’s transcriptional activity at the genomic scale according to RNA sequencing analyses, blocks autophagy in a dose-dependent manner, and increases the sensitivity of glioblastoma to temozolomide in vivo. Together, this work reveals that TFEB is targetable and presents the first direct TFEB inhibitor EO, a drug compound with great potential to benefit a wide range of cancer therapies by inhibiting autophagy.
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影响因子：
29
作者：
Kimmelman AC;White E
通讯作者：
White E
影响因子：
28.2
作者：
Collisson EA;Trejo CL;Silva JM;Gu S;Korkola JE;Heiser LM;Charles RP;Rabinovich BA;Hann B;Dankort D;Spellman PT;Phillips WA;Gray JW;McMahon M
通讯作者：
McMahon M
影响因子：
28.2
作者：
Karsli-Uzunbas G;Guo JY;Price S;Teng X;Laddha SV;Khor S;Kalaany NY;Jacks T;Chan CS;Rabinowitz JD;White E
通讯作者：
White E
影响因子：
13.3
作者：
Mahalingam, Devalingam;Mita, Monica;Carew, Jennifer S.
通讯作者：
Carew, Jennifer S.
影响因子：
64.5
作者：
Green DR;Levine B
通讯作者：
Levine B