Research Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, China.
Key Laboratory of Tumor Gene Diagnosis, Prevention and Therapy, Clinical Oncology Research Center, Shijiazhuang, 050000, China.
Oncol Res. 2024 Oct 16;32(11):1791-1802. doi: 10.32604/or.2024.049348. eCollection 2024.
Triple-negative breast cancer (TNBC) is a heterogeneous, recurring cancer characterized by a high rate of metastasis, poor prognosis, and lack of efficient therapies. KBU2046, a small molecule inhibitor, can inhibit cell motility in malignant tumors, including breast cancer. However, the specific targets and the corresponding mechanism of its function remain unclear.
In this study, we employed (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium) (MTS) assay and transwell assay to investigate the impact of KBU2046 on the proliferation and migration of TNBC cells . RNA-Seq was used to explore the targets of KBU2046 that inhibit the motility of TNBC. Finally, confirmed the predicted important signaling pathways through RT-qPCR and western blotting.
In this study, we found that KBU2046 functioned as a novel transforming growth factor-β (TGF-β1) inhibitor, effectively suppressing tumor cell motility . Mechanistically, it directly down-regulated leucine-rich repeat-containing 8 family, member E (LRRC8E), latent TGFβ-binding protein 3 (LTBP3), dynein light chain 1 (DNAL1), and MAF family of bZIP transcription factors (MAFF) genes, along with reduced protein expression of the integrin family. Additionally, KBU2046 decreased phosphorylation levels of Raf and ERK. This deactivation of the ERK signaling pathway impeded cancer invasion and metastasis.
In summary, these findings advocate for the utilization of TGF-β1 as a diagnostic and prognostic biomarker and as a therapeutic target in TNBC. Furthermore, our data underscore the potential of KBU2046 as a novel therapeutic strategy for combating cancer metastasis.
三阴性乳腺癌（TNBC）是一种异质性、复发性癌症，其特征是转移率高、预后差且缺乏有效的治疗方法。小分子抑制剂 KBU2046 可抑制包括乳腺癌在内的恶性肿瘤细胞的运动性。然而，其作用的具体靶点和相应机制尚不清楚。
在本研究中，我们采用（3-(4,5-二甲基噻唑-2-基）-5-(3-羧基甲氧基苯基)-2-(4-磺基苯基)-2H 四唑）（MTS）测定法和 Transwell 测定法研究 KBU2046 对 TNBC 细胞增殖和迁移的影响。RNA-Seq 用于探索抑制 TNBC 运动性的 KBU2046 靶标。最后，通过 RT-qPCR 和 Western blot 验证了预测的重要信号通路。
本研究发现，KBU2046 作为一种新型转化生长因子-β（TGF-β1）抑制剂，可有效抑制肿瘤细胞的运动性。其作用机制为直接下调富含亮氨酸重复的 8 家族成员 E（LRRC8E）、潜伏转化生长因子-β 结合蛋白 3（LTBP3）、动力蛋白轻链 1（DNAL1）和 MAFF 家族 bZIP 转录因子（MAFF）基因，同时下调整合素家族的蛋白表达。此外，KBU2046 降低了 Raf 和 ERK 的磷酸化水平。ERK 信号通路的失活阻碍了癌症的侵袭和转移。
综上所述，这些发现主张将 TGF-β1 作为 TNBC 的诊断和预后生物标志物以及治疗靶点。此外，我们的数据强调了 KBU2046 作为一种新型治疗策略用于治疗癌症转移的潜力。
