Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, Jilin, China (mainland).
The Bethune Institute of Epigenetic Medicine, The First Hospital of Jilin University, Changchun, Jilin, China (mainland).
Med Sci Monit. 2020 Aug 17;26:e927106. doi: 10.12659/MSM.927106.
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is a life-threatening digestive tract malignancy with no known curative treatment. This study aimed to investigate the antineoplastic effects of omipalisib and its underlying molecular mechanisms in ESCC using a high throughput screen. MATERIAL AND METHODS MTT assay and clone formation were used to determine cell viability and proliferation. Flow cytometry was conducted to detect cell cycle distribution and apoptosis. Global gene expression and mRNA expression levels were determined by RNA sequencing and real-time PCR, respectively. Protein expression was evaluated in the 4 ESCC cell lines by Western blot analysis. Finally, a xenograft nude mouse model was used to evaluate the effect of omipalisib on tumor growth in vivo. RESULTS In the pilot screening of a 1404-compound library, we demonstrated that omipalisib markedly inhibited cell proliferation in a panel of ESCC cell lines. Mechanistically, omipalisib induced G₀/G₁ cell cycle arrest and apoptosis. RNA-seq, KEGG, and GSEA analyses revealed that the PI3K/AKT/mTOR pathway is the prominent target of omipalisib in ESCC cells. Treatment with omipalisib decreased expression of p-AKT, p-4EBP1, p-p70S6K, p-S6, and p-ERK, therefore disrupting the activation of PI3K/AKT/mTOR and ERK signaling. In the nude mouse xenograft model, omipalisib significantly suppressed the tumor growth in ESCC tumor-bearing mice without obvious adverse effects. CONCLUSIONS Omipalisib inhibited the proliferation and growth of ESCC by disrupting PI3K/AKT/mTOR and ERK signaling. The present study supports the rationale for using omipalisib as a therapeutic approach in ESCC patients. Further clinical studies are needed.
食管鳞状细胞癌（ESCC）是一种危及生命的消化道恶性肿瘤，目前尚无已知的治愈方法。本研究旨在通过高通量筛选来研究 omipalisib 在 ESCC 中的抗肿瘤作用及其潜在的分子机制。
MTT 法和集落形成实验用于测定细胞活力和增殖；流式细胞术检测细胞周期分布和凋亡；通过 RNA 测序和实时 PCR 分别测定全基因表达和 mRNA 表达水平；Western blot 分析评估 4 种 ESCC 细胞系中的蛋白质表达；最后，通过裸鼠异种移植模型评估 omipalisib 在体内对肿瘤生长的影响。
在对 1404 种化合物文库的初步筛选中，我们证明 omipalisib 可显著抑制一系列 ESCC 细胞系的增殖。机制上，omipalisib 诱导 G₀/G₁ 细胞周期阻滞和细胞凋亡。RNA-seq、KEGG 和 GSEA 分析显示，PI3K/AKT/mTOR 通路是 omipalisib 在 ESCC 细胞中的主要靶点。omipalisib 处理降低了 p-AKT、p-4EBP1、p-p70S6K、p-S6 和 p-ERK 的表达，从而破坏了 PI3K/AKT/mTOR 和 ERK 信号的激活。在裸鼠异种移植模型中，omipalisib 显著抑制了 ESCC 荷瘤小鼠的肿瘤生长，而没有明显的不良反应。
omipalisib 通过破坏 PI3K/AKT/mTOR 和 ERK 信号抑制 ESCC 的增殖和生长。本研究支持将 omipalisib 作为 ESCC 患者的治疗方法的原理。需要进一步的临床研究。
