University of Groningen, Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, the Netherlands.
University of Groningen, Department of Chemical and Pharmaceutical Biology, Groningen Research Institute of Pharmacy, the Netherlands.
Biochem Pharmacol. 2020 May;175:113914. doi: 10.1016/j.bcp.2020.113914. Epub 2020 Mar 12.
Transcriptional coactivators p300 and CBP catalyze the acetylation of lysine residues in histone proteins. Upregulation of p300 and CBP has been associated with lung, colorectal and hepatocellular cancer, indicating an important role of p300 and CBP in tumorigenesis. Recently, the novel p300 and CBP-selective inhibitor A485 became available, which was shown to inhibit proliferation of 124 different cancer cell lines. Here, we found that downregulation of EP300 or CREBBP enhances apoptosis upon TRAIL stimulation in non-small-cell lung cancer (NSCLC) cells. A485 upregulates pro- and anti-apoptotic genes at the mRNA level, implying an apoptosis-modulating effect in NSCLC cells. However, A485 alone does not induce apoptosis. Interestingly, we observed that the number of apoptotic cells increases upon combined treatment with A485 and TRAIL. Therefore, A485, as a TRAIL-sensitizer, was used in combination with TRAIL in wild type of NSCLC cell lines (HCC827 and H1650) and cells with acquired erlotinib resistance (HCC827-ER and H1650-ER). Our results show that the combination of A485 and TRAIL synergistically increases cell death and inhibits long-term cell proliferation. Furthermore, this combination inhibits the growth of 3D spheroids of EGFR-TKI-resistant cells. Taken together, we demonstrate a successful combination of A485 and TRAIL in EGFR-TKI-sensitive and resistant NSCLC cells.
转录共激活因子 p300 和 CBP 催化组蛋白赖氨酸残基的乙酰化。p300 和 CBP 的上调与肺癌、结直肠癌和肝细胞癌有关，表明 p300 和 CBP 在肿瘤发生中具有重要作用。最近，新型的 p300 和 CBP 选择性抑制剂 A485 已经问世，它被证明可以抑制 124 种不同的癌细胞系的增殖。在这里，我们发现 EP300 或 CREBBP 的下调增强了 TRAIL 刺激非小细胞肺癌（NSCLC）细胞中的细胞凋亡。A485 在 mRNA 水平上调促凋亡和抗凋亡基因，暗示其在 NSCLC 细胞中具有凋亡调节作用。然而，A485 本身并不能诱导细胞凋亡。有趣的是，我们观察到在用 A485 和 TRAIL 联合处理时，凋亡细胞的数量增加。因此，A485 作为 TRAIL 增敏剂，与 TRAIL 联合用于野生型 NSCLC 细胞系（HCC827 和 H1650）和获得厄洛替尼耐药的细胞（HCC827-ER 和 H1650-ER）中。我们的结果表明，A485 和 TRAIL 的联合使用协同增加了细胞死亡并抑制了长期细胞增殖。此外，该联合抑制了 EGFR-TKI 耐药细胞的 3D 球体生长。总之，我们证明了 A485 和 TRAIL 在 EGFR-TKI 敏感和耐药的 NSCLC 细胞中的成功联合。
