羟基酪醇和橄榄苦苷通过诱导自噬抑制 MDA-MB-231 三阴性乳腺癌细胞的迁移和侵袭。

Hydroxytyrosol and Oleuropein Inhibit Migration and Invasion of MDA-MB-231 Triple-Negative Breast Cancer Cell via Induction of Autophagy.

机构信息

Animal, Plant and Food Inspection Center, Nanjing Customs, 39 Chuangzhi Rd., Nanjing 210017, China.

Key Lab of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, 101 Longmian Avenue, Nanjing 211166, China.

出版信息

Anticancer Agents Med Chem. 2019;19(16):1983-1990. doi: 10.2174/1871520619666190722101207.

DOI:10.2174/1871520619666190722101207

PMID:31333142

Abstract

BACKGROUND

Breast Cancer (BC) is the leading cause of cancer-related deaths among women. As such, novel chemotherapeutic agents are urgently needed, especially for Triple-Negative Breast Cancer (TNBC). Hydroxytyrosol (HT) and Oleuropein (OL) are rich in olive oil, which is associated with a low occurrence of BC. However, the effects and mechanisms of action of HT and OL in BC cells are still unclear. This study aimed to explore the molecular mechanisms underlying the antitumor effect of HT and OL in TNBC.

METHODS

TNBC MDA-MB-231 cells were treated with HT and OL in combination with Hepatocyte Growth Factor (HGF), rapamycin (Rapa, an inducer of autophagy) or 3-methyladenine (3-MA, an inhibitor of autophagy). Cell viability, migration, invasion, and autophagy signaling were analyzed by scratch assays, transwell migration assays, and Western blot analysis.

RESULTS

Treatment with HT or OL reduced MDA-MB-231 cell viability in a dose-dependent manner. MDAMB- 231 cells were more sensitive to HT treatment than OL treatment. Rapa treatment could significantly block HGF-induced MDA-MB-231 cell migration and invasion, suggesting that inhibition of autophagy could promote migration and invasion. Moreover, HT or OL treatment significantly suppressed HGF or 3-MA induced cell migration and invasion by reversing LC3-II/LC3-I and Beclin-1 downregulation and reversing p62 upregulation.

CONCLUSION

These data indicated that HT and OL may inhibit migration and invasion of TNBC cells by activating autophagy. These findings provide potential therapeutic strategies that target autophagy to limit the pathogenesis and progression of BC.

摘要

背景

乳腺癌（BC）是女性癌症相关死亡的主要原因。因此，急需新型化疗药物，特别是用于三阴性乳腺癌（TNBC）。羟基酪醇（HT）和橄榄苦苷（OL）富含橄榄油，橄榄油与 BC 的低发病率有关。然而，HT 和 OL 在 BC 细胞中的作用和作用机制尚不清楚。本研究旨在探讨 HT 和 OL 在 TNBC 中的抗肿瘤作用的分子机制。

方法

用 HT 和 OL 联合肝细胞生长因子（HGF）、雷帕霉素（Rapa，自噬诱导剂）或 3-甲基腺嘌呤（3-MA，自噬抑制剂）处理 TNBC MDA-MB-231 细胞。通过划痕试验、Transwell 迁移试验和 Western blot 分析分析细胞活力、迁移、侵袭和自噬信号。

结果

HT 或 OL 处理以剂量依赖性方式降低 MDA-MB-231 细胞活力。MDA-MB-231 细胞对 HT 处理比 OL 处理更敏感。Rapa 处理可显著阻断 HGF 诱导的 MDA-MB-231 细胞迁移和侵袭，表明自噬抑制可促进迁移和侵袭。此外，HT 或 OL 处理通过逆转 LC3-II/LC3-I 和 Beclin-1 下调以及逆转 p62 上调，显著抑制 HGF 或 3-MA 诱导的细胞迁移和侵袭。