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Efficacy of a small molecule inhibitor of the transcriptional cofactor PC4 in prevention and treatment of non-small cell lung cancer.

转录辅因子PC4 小分子抑制剂防治非小细胞肺癌的疗效。

  • 影响因子:3.02
  • DOI:10.1371/journal.pone.0230670
  • 作者列表:"Zhang Y","Pavlov A","Malik S","Chen H","Kim N","Li Z","Zhang X","DePamphilis ML","Roeder RG","Ge H
  • 发表时间:2020-03-31
Abstract

:The human positive coactivator 4 (PC4) was originally identified as a multi-functional cofactor capable of mediating transcription activation by diverse gene- and tissue-specific activators. Recent studies suggest that PC4 might also function as a novel cancer biomarker and therapeutic target for different types of cancers. siRNA knockdown studies indicated that down-regulation of PC4 expression could inhibit tumorigeneicity of A549 non-small cell lung cancer tumor model in nude mice. Here we show that AG-1031, a small molecule identified by high throughput screening, can inhibit the double-stranded DNA binding activity of PC4, more effectively than its single-stranded DNA binding activity. AG-1031 also specifically inhibited PC4-dependent transcriptional activation in vitro using purified transcription factors. AG-1031 inhibited proliferation of several cultured cell lines derived from non-small cell lung cancers (NSCLC) and growth of tumors that formed from A549 cell xenografts in immuno-compromised mice. Moreover, pre-injection of AG-1031 in these mice not only reduced tumor size, but also prevented tumor formation in 20% of the animals. AG-1031 treated A549 cells and tumors from AG-1031 treated animals showed a significant decrease in the levels of both PC4 and VEGFC, a key mediator of angiogenesis in cancer. On the other hand, all tested mice remained constant weight during animal trials. These results demonstrated that AG-1031 could be a potential therapy for PC4-positive NSCLC.

摘要

: 人阳性辅激活因子 4 (PC4) 最初被鉴定为能够介导多种基因和组织特异性激活剂的转录激活的多功能辅因子。最近的研究表明,PC4 也可能作为一种新的癌症生物标志物和不同类型癌症的治疗靶点。SiRNA敲除研究表明,下调PC4 表达可抑制A549 非小细胞肺癌裸鼠肿瘤模型的致瘤性。在这里,我们证明了通过高通量筛选鉴定的小分子AG-1031 可以比其单链DNA结合活性更有效地抑制PC4 的双链DNA结合活性。AG-1031 还使用纯化的转录因子在体外特异性抑制PC4-dependent的转录激活。AG-1031 抑制来自非小细胞肺癌 (NSCLC) 的几种培养细胞系的增殖和在免疫受损小鼠中由A549 细胞异种移植物形成的肿瘤的生长。此外,在这些小鼠中预先注射AG-1031 不仅减小了肿瘤大小,而且在 20% 的动物中防止了肿瘤形成。AG-1031 处理的A549 细胞和来自AG-1031 处理的动物的肿瘤显示PC4 和VEGFC (癌症中血管生成的关键介质) 的水平显著降低。另一方面,所有测试的小鼠在动物试验期间保持恒定体重。这些结果表明AG-1031 可能是PC4-positive NSCLC的潜在疗法。

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肺肿瘤方向

肺肿瘤,又叫支气管肺癌,是常见的恶性肿瘤之一。肺肿瘤的治疗为包括手术、中药、放疗、化疗及免疫等多学科的综合治疗。

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