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

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.

Potential Protective Role Exerted by Secoiridoids from Olea europaea L. in Cancer, Cardiovascular, Neurodegenerative, Aging-Related, and Immunoinflammatory Diseases

“…Besides, OL produced tissue inhibitors of metalloproteinases (TIMPs) overexpression and metalloproteinases (MMPs) genes down-regulation, which could help in the prevention of breast cancer metastasis [82]. Similarly, OL treatment reduced MDA-MB-231 cell viability in a dose-dependent manner and significantly suppressed hepatocyte growth factor (HGF) and 3-methyladenine (3-MA) inducing cell migration and invasion [90].…”

Oleuropein, a Bioactive Compound from Olea europaea L., as a Potential Preventive and Therapeutic Agent in Non-Communicable Diseases

“…Recently HY et al [113] found that inhibition of autophagy in a Triple-Negative Breast Cancer cell line promoted migration and invasion, as demonstrated by exposition with Hepatocyte Growth Factor (HGT), or 3-methyladenine, an inhibitor of autophagy. On the contrary, the co-treatment with HT or Ole significantly suppressed HGF or 3-MA induced cell migration and invasion, by reversing LC3 II/I and Beclin-1 downregulation, and p62 upregulation.…”

Crosstalk between hydroxytyrosol, a major olive oil phenol, and HIF-1 in MCF-7 breast cancer cells

“…However, inactivation of autophagy has been associated with shortened survival of breast cancer patients 63 and the loss of autophagy-related genes increases the aggressive development of HER2-positive breast cancer 64 . Several reports point to HT as an inducer of autophagy 65,66 . Although the study of the effect of HT on autophagy in hypoxic conditions is beyond of this work, our results seem to indicate that HT could affect this process.…”