Department of Hematology and Breast Cancer, Cancer Hospital of China Medical University, Liaoning Cancer Hospital and Institute, 44 Xiaoheyan Road, Shenyang, 110042, People's Republic of China.
Mol Cell Biochem. 2018 Dec;449(1-2):285-294. doi: 10.1007/s11010-018-3365-1. Epub 2018 May 14.
Biglycan (BGN) is overexpressed in cancer stem cells of colon cancer and induces the activation of NF-κB pathway which contributes to the chemotherapy resistance of diverse cancer types. Therefore, we hypothesized that the overexpression of BGN also promoted the development of multiple drug resistance (MDR) in colon cancer via NF-κB pathway. The expression of BGN was bilaterally modulated in colon cancer cell lines HT-29 and SW-480 and the effect of treatments on the cell proliferation and resistance to 5-FU was assessed. Moreover, the role of NF-κB signaling in the BGN-mediated formation of MDR was further investigated by subjecting BGN-overexpressed SW-480 cells to the co-treatment of chemo-agents and NF-κB inhibitor, PDTC. The inhibition of BGN expression decreased the proliferation potential of HT-29 cells while the induction of BGN expression increased the potential of SW-480 cells. BGN knockdown increased HT-29 cells' sensitivity to 5-FU, represented by the lower colony number and higher apoptotic rate. To the contrary, BGN overexpression promoted the resistance of SW-480 cells to 5-FU. The effect of BGN modulation on colon cancer cells was associated with the changes in apoptosis and NF-κB pathways: BGN inhibition increased the expressions of pro-apoptosis indicators and suppressed NF-κB pathway activity while BGN overexpression had the opposite effect. It was also found that the BGN-mediated formation of MDR was impaired when NF-κB pathway was blocked. Findings outlined in the current study showed that BGN contributed to the formation of chemotherapy resistance in colon cancer cells by activating NF-κB signaling.
核心蛋白聚糖 (BGN) 在结肠癌的肿瘤干细胞中过表达，并诱导 NF-κB 通路的激活，这有助于多种癌症类型的化疗耐药性。因此，我们假设 BGN 的过表达也通过 NF-κB 通路促进了结肠癌的多药耐药 (MDR) 的发展。我们在结肠癌细胞系 HT-29 和 SW-480 中双侧调节 BGN 的表达，并评估了处理对细胞增殖和对 5-FU 耐药性的影响。此外，我们通过使 BGN 过表达的 SW-480 细胞接受化疗药物和 NF-κB 抑制剂 PDTC 的联合治疗，进一步研究了 NF-κB 信号在 BGN 介导的 MDR 形成中的作用。BGN 表达的抑制降低了 HT-29 细胞的增殖潜力，而 BGN 表达的诱导增加了 SW-480 细胞的增殖潜力。BGN 敲低增加了 HT-29 细胞对 5-FU 的敏感性，表现为更少的集落数和更高的凋亡率。相反，BGN 过表达促进了 SW-480 细胞对 5-FU 的耐药性。BGN 调节对结肠癌细胞的影响与凋亡和 NF-κB 通路的变化有关：BGN 抑制增加了促凋亡指标的表达并抑制了 NF-κB 通路活性，而 BGN 过表达则产生相反的效果。还发现，当 NF-κB 通路被阻断时，BGN 介导的 MDR 形成受到损害。本研究的结果表明，BGN 通过激活 NF-κB 信号促进了结肠癌细胞化疗耐药性的形成。
