Department of General Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 201508, P.R. China.
Oncol Rep. 2022 Oct;48(4). doi: 10.3892/or.2022.8397. Epub 2022 Sep 7.
The present study aimed to assess the anticancer cell and anticancer stem cell (CSC) effects of GANT61, and its regulatory influence on the Wnt/β‑catenin and Notch signalling pathways in colorectal cancer (CRC). HT‑29 and HCT‑116 cells were treated with 0, 2.5, 5, 10, 20 or 40 µM GANT61, after which relative cell viability and the expression of Gli1, β‑catenin and Notch1, as well as the percentage of CD133 cells, were detected. Subsequently, HT‑29/HCT‑116 cells and CSCs were treated with 20 µM GANT61, 10 mM of the Wnt/β‑catenin pathway agonist HLY78, and 30 mM of the Notch pathway agonist JAG1 (alone or in combination), which was followed by the assessment of cell viability and apoptosis. In both cell lines, GANT61 reduced relative cell viability in a time‑ and dose‑dependent manner, inhibited Gli1, β‑catenin and Notch1 expression, and decreased the percentage of CD133 cells in a dose‑dependent manner. Furthermore, HLY78 and JAG1 were both found to improve the relative viability, while downregulating the apoptosis of untreated and GANT61‑treated HT‑29 and HCT‑116 cells. Moreover, Wnt/β‑catenin and Notch signalling pathway activity were upregulated in CSCs isolated from HT‑29 and HCT‑116 cells, compared with the associated control groups. GANT61 also reduced the viability of HT‑29 and HCT‑116 cells and increased apoptosis, whereas HLY78 and JAG1 treatment resulted in the opposite effect. Moreover, both HLY78 and JAG1 attenuated the effects of GANT61 on cellular viability and apoptosis. In conclusion, GANT61 was found to effectively eliminate cancer cells and CSCs by blocking the Wnt/β‑catenin and Notch signalling pathways in CRC.
本研究旨在评估 GANT61 对癌细胞和癌症干细胞（CSC）的作用，及其对结直肠癌（CRC）中 Wnt/β-catenin 和 Notch 信号通路的调控影响。用 0、2.5、5、10、20 或 40μM GANT61 处理 HT-29 和 HCT-116 细胞后，检测相对细胞活力以及 Gli1、β-catenin 和 Notch1 的表达情况，以及 CD133 细胞的百分比。随后，用 20μM GANT61、10mM Wnt/β-catenin 通路激动剂 HLY78 和 30mM Notch 通路激动剂 JAG1（单独或联合）处理 HT-29/HCT-116 细胞和 CSCs，然后评估细胞活力和细胞凋亡情况。在两种细胞系中，GANT61 均呈时间和剂量依赖性地降低相对细胞活力，抑制 Gli1、β-catenin 和 Notch1 的表达，并呈剂量依赖性降低 CD133 细胞的百分比。此外，发现 HLY78 和 JAG1 均能提高未经处理和 GANT61 处理的 HT-29 和 HCT-116 细胞的相对活力，同时下调其细胞凋亡。此外，与相应的对照组相比，从 HT-29 和 HCT-116 细胞中分离出的 CSCs 中 Wnt/β-catenin 和 Notch 信号通路活性上调。GANT61 还降低了 HT-29 和 HCT-116 细胞的活力并增加了细胞凋亡，而 HLY78 和 JAG1 处理则产生相反的效果。此外，HLY78 和 JAG1 均减弱了 GANT61 对细胞活力和细胞凋亡的影响。综上所述，GANT61 通过阻断 CRC 中的 Wnt/β-catenin 和 Notch 信号通路，有效消除癌细胞和 CSCs。
