胸腺醌通过抑制自噬、Beclin-1 和 LC3 抑制 MDA-MB-231 三阴性乳腺癌细胞的增殖和迁移。
Thymoquinone Inhibits Proliferation and Migration of MDA-MB-231 Triple Negative Breast Cancer Cells by Suppressing Autophagy, Beclin-1 and LC3.
机构信息
Betul-Ziya Eren Genome and Stem Cell Center, University of Erciyes, Kayseri, Turkey.
Departments of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, United States.
出版信息
Anticancer Agents Med Chem. 2021;21(3):355-364. doi: 10.2174/1871520620666200807221047.
BACKGROUND
Triple Negative Breast Cancer (TNBC) is an aggressive and highly heterogeneous subtype of breast cancer associated with poor prognosis. A better understanding of the biology of this complex cancer is needed to develop novel therapeutic strategies for the improvement of patient survival. We have previously demonstrated that Thymoquinone (TQ), the major phenolic compound found in Nigella sativa, induces anti-proliferative and anti-metastatic effects and inhibits in vivo tumor growth in orthotopic TNBC models in mice. Also, we have previously shown that Beclin-1 and LC3 autophagy genes contributes to TNBC cell proliferation, migration and invasion, suggesting that Beclin-1 and LC3 genes provide proto-oncogenic effects in TNBC. However, the role of Beclin-1 and LC3 in mediating TQ-induced anti-tumor effects in TNBC is not known.
OBJECTIVE
To investigate the effects of TQ on the major autophagy mediators, Beclin-1 and LC3 expression, as well as autophagic activity in TNBC cells.
METHODS
Cell proliferation, colony formation, migration and autophagy activity were evaluated using MTS cell viability, colony formation assay, wound healing and acridine orange staining assays, respectively. Western blotting and RT-PCR assays were used to investigate LC3 and Beclin-1 protein and gene expressions, respectively, in MDA-MB-231 TNBC cells in response to TQ treatments.
RESULTS
TQ treatment significantly inhibited cell proliferation, colony formation, migration and autophagic activity of MDA-MB-231 cells and suppressed LC3 and Beclin-1 expressions. Furthermore, TQ treatment led to the inhibition of Integrin-β1, VEGF, MMP-2 and MMP-9 in TNBC cells.
CONCLUSION
TQ inhibits autophagic activity and expression of Beclin-1 and LC3 in TNBC cells and suppresses pathways related to cell migration/invasion and angiogenesis, including Integrin-β1, VEGF, MMP-2 and MMP- 9, suggesting that TQ may be used to control autophagic activity and oncogenic signaling in TNBC.
背景
三阴性乳腺癌（TNBC）是一种侵袭性和高度异质性的乳腺癌亚型，与预后不良相关。为了开发新的治疗策略来提高患者的生存率，需要更好地了解这种复杂癌症的生物学特性。我们之前已经证明，百里醌（TQ），黑种草中发现的主要酚类化合物，可诱导抗增殖和抗转移作用，并抑制小鼠原位 TNBC 模型中的体内肿瘤生长。此外，我们之前还表明，Beclin-1 和 LC3 自噬基因有助于 TNBC 细胞的增殖、迁移和侵袭，这表明 Beclin-1 和 LC3 基因在 TNBC 中提供原癌基因效应。然而，Beclin-1 和 LC3 在介导 TQ 诱导的 TNBC 抗肿瘤作用中的作用尚不清楚。
目的
研究 TQ 对 TNBC 细胞中主要自噬介质 Beclin-1 和 LC3 表达以及自噬活性的影响。
方法
使用 MTS 细胞活力测定法、集落形成测定法、划痕愈合测定法和吖啶橙染色测定法分别评估细胞增殖、集落形成、迁移和自噬活性。Western blot 和 RT-PCR 测定法分别用于研究 MDA-MB-231 TNBC 细胞对 TQ 处理的 LC3 和 Beclin-1 蛋白和基因表达。
结果
TQ 处理显著抑制 MDA-MB-231 细胞的增殖、集落形成、迁移和自噬活性，并抑制 LC3 和 Beclin-1 的表达。此外，TQ 处理导致 TNBC 细胞中整合素-β1、VEGF、MMP-2 和 MMP-9 的抑制。
结论
TQ 抑制 TNBC 细胞中的自噬活性和 Beclin-1 和 LC3 的表达，并抑制与细胞迁移/侵袭和血管生成相关的途径，包括整合素-β1、VEGF、MMP-2 和 MMP-9，表明 TQ 可用于控制 TNBC 中的自噬活性和致癌信号。
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