Graduate Institute of Natural Products, Department of Biomedical Science and Environmental Biology, Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Molecules. 2013 Aug 22;18(9):10242-53. doi: 10.3390/molecules180910242.
Cancer stem cells (CSCs) are a small subset of cancer cells with indefinite potential for self-renewal and the capacity to drive tumorigenesis. Brefeldin A (BFA) is an antibiotic that is known to block protein transport and induce endoplasmic reticulum (ER) stress in eukaryotic cells, but its effects on colorectal CSCs are unknown. We investigated the inhibitory effect of BFA on human colorectal cancer Colo 205 cells. We found that BFA effectively reduced the survival of suspension Colo 205 cells (IC₅₀ = ~15 ng/mL) by inducing apoptosis, and inhibited the clonogenic activity of Colo 205 CSCs in tumorsphere formation assay and soft agar colony formation assay in the same nanogram per milliliter range. We also discovered that at such low concentrations, BFA effectively induced endoplasmic reticulum (ER) stress response as indicated by the increased mRNA expression of ER stress-related genes, such as glucose-regulated protein 78 (GRP78), X-box binding protein 1 (XBP1), and C/EBP homologous protein (CHOP). Finally, we found that BFA reduced the activity of matrix metallopeptidase 9 (MMP-9). These findings suggest that BFA can effectively suppress the progression of colorectal cancer during the tumorigenesis and metastasis stages. These results may lead to the development of novel therapies for the treatment of colorectal cancer.
癌症干细胞（CSCs）是一小部分具有无限自我更新潜力和驱动肿瘤发生能力的癌细胞。布雷菲德菌素 A（BFA）是一种抗生素，已知可阻断真核细胞中的蛋白质运输并诱导内质网（ER）应激，但它对结直肠 CSCs 的影响尚不清楚。我们研究了 BFA 对人结直肠癌细胞 Colo 205 的抑制作用。我们发现 BFA 通过诱导细胞凋亡有效降低悬浮培养的 Colo 205 细胞的存活率（IC₅₀≈15ng/mL），并在肿瘤球形成实验和软琼脂集落形成实验中以相同的纳克/毫升范围内抑制 Colo 205 CSCs 的集落形成活性。我们还发现，在如此低的浓度下，BFA 有效诱导内质网（ER）应激反应，如 ER 应激相关基因的 mRNA 表达增加，如葡萄糖调节蛋白 78（GRP78）、X 盒结合蛋白 1（XBP1）和 C/EBP 同源蛋白（CHOP）。最后，我们发现 BFA 降低了基质金属蛋白酶 9（MMP-9）的活性。这些发现表明，BFA 可以有效抑制结直肠癌在肿瘤发生和转移阶段的进展。这些结果可能导致开发治疗结直肠癌的新疗法。
