Cancer Biology Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, Odisha, 751023, India.
Tumor Microenvironment and Animal Models Group, Institute of Life Sciences, Nalco Square, Bhubaneswar, 751023, India.
Cell Oncol (Dordr). 2022 Aug;45(4):659-675. doi: 10.1007/s13402-022-00690-9. Epub 2022 Jul 14.
Ecotropic viral integration site 1 (EVI1) is an oncogenic transcription factor that has been attributed to chemotherapy resistance in different cancers. As yet, however, its role in colon cancer drug resistance is not completely understood. Here, we set out to investigate the functional and therapeutic relevance of EVI1 in colon cancer drug resistance.
The EVI1 gene was knocked down in colon cancer cells that were subsequently tested for susceptibility to irinotecan using in vitro assays and in vivo subcutaneous mouse colon cancer models. The effect of EVI1 knockdown on the AKT-mTOR signaling pathway was assessed using cell line models, immunohistochemistry and bioinformatics tools. The anti-proliferative activity of AKT inhibitor GSK690693 and its combination with irinotecan was tested in colon cancer cell line models (2D and 3D). Finally, the therapeutic efficacy of GSK690693 and its combination with irinotecan was evaluated in xenografted EVI1 expressing colon cancer mouse models.
We found that EVI1 knockdown decreased cancer stem cell-like properties and improved irinotecan responses in both cell line and subcutaneous mouse models. In addition, we found that EVI1 downregulation resulted in inhibition of AKT/mTOR signaling and RICTOR expression. Knocking down RICTOR expression increased the cytotoxic effects of irinotecan in EVI1 downregulated colon cancer cells. Co-treatment with irinotecan and ATP-competitive AKT inhibitor GSK690693 significantly reduced colon cancer cell survival and tumor progression rates.
Inhibition of the AKT signaling cascade by GSK690693 may serve as an alternative to improve the irinotecan response in EVI1-expressing colon cancer cells.
嗜性逆转录病毒整合位点 1（EVI1）是一种致癌转录因子，它与不同癌症的化疗耐药性有关。然而，目前尚不清楚其在结肠癌耐药性中的作用。在这里，我们旨在研究 EVI1 在结肠癌耐药性中的功能和治疗相关性。
在结肠癌细胞中敲低 EVI1 基因，然后使用体外测定和体内皮下结肠癌小鼠模型测试其对伊立替康的敏感性。使用细胞系模型、免疫组织化学和生物信息学工具评估 EVI1 敲低对 AKT-mTOR 信号通路的影响。在结肠癌细胞系模型（2D 和 3D）中测试 AKT 抑制剂 GSK690693 的抗增殖活性及其与伊立替康的组合。最后，在异种移植表达 EVI1 的结肠癌小鼠模型中评估 GSK690693 及其与伊立替康的组合的治疗效果。
我们发现 EVI1 敲低降低了癌症干细胞样特性并改善了细胞系和皮下小鼠模型中的伊立替康反应。此外，我们发现 EVI1 下调导致 AKT/mTOR 信号和 RICTOR 表达抑制。敲低 RICTOR 表达增加了 EVI1 下调的结肠癌细胞中伊立替康的细胞毒性作用。伊立替康与 ATP 竞争性 AKT 抑制剂 GSK690693 的联合治疗显著降低了结肠癌细胞的存活率和肿瘤进展率。
通过 GSK690693 抑制 AKT 信号级联可能是改善 EVI1 表达的结肠癌细胞对伊立替康反应的一种替代方法。
