Resveratrol reverses TGF‐β1‐mediated invasion and metastasis of breast cancer cells via the SIRT3/AMPK/autophagy signal axis

• Published in: Phytotherapy research Vol. 37; no. 1; pp. 211 - 230
• Main Authors: Wang, Jia, Huang, Ping, Pan, Xiafang, Xia, Chunhua, Zhang, Hong, Zhao, Han, Yuan, Zhao, Liu, Jianming, Meng, Chao, Liu, Fanglan
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 01.01.2023; Wiley Subscription Services, Inc
• Subjects: AMP-Activated Protein Kinases; Animals; Anticancer properties; autophagosomes; Autophagy; Breast cancer; breast neoplasms; Cell Line, Tumor; Cell Movement; Cell proliferation; Epithelial-Mesenchymal Transition; Growth factors; Humans; Lung cancer; Metastases; Metastasis; Mice; Molecular modelling; neoplasm cells; neoplasm progression; Neoplasms; Phagosomes; Phosphorylation; phytotherapy; Proteins; Resveratrol; Resveratrol - pharmacology; RNA; siRNA; SIRT3; Sirtuin 3; Therapeutic targets; Transforming Growth Factor beta1 - metabolism; Transforming growth factor-b1; tumor metastasis; Tumors; Xenografts; Xenotransplantation; breast cancer; epithelial-mesenchymal transition; autophagy; tumor metastasis; resveratrol; SIRT3
• ISSN: 0951-418X; 1099-1573; 1099-1573
• DOI: 10.1002/ptr.7608

Resveratrol (Resv) has antitumorigenic and antimetastatic activities; however, the molecular mechanisms underlying the inhibitory effects of Resv on the invasion and metastasis of breast cancer cells are still a subject of debate. In our study, we demonstrated that Resv inhibited tumor cell proliferation and tumor growth. It also suppressed invasion and pulmonary metastasis of breast cancer by reversing the transforming growth factor beta 1 (TGF‐β1)‐mediated EMT process. Meanwhile, the anticarcinogenic effects of Resv were abolished by the autophagy blocker 3‐methyladenine (3‐MA) or Beclin 1 small interfering RNA. Moreover, Resv upregulated autophagy‐related genes and protein levels and induced the formation of autophagosomes in 4T1 breast cancer cells and xenograft mice, suggesting that autophagy was involved in the anticarcinogenic activities of Resv in both models. In addition, Resv‐induced autophagy by increasing the expression of SIRT3 and phosphorylated AMPK. SIRT3 knockdown reduced AMPK phosphorylation and autophagy‐related proteins levels, and suppressed the anticancer effects of Resv, demonstrating that the inhibitory effects of Resv on tumor progression were mediated via the SIRT3/AMPK/autophagy pathway. Taken together, our study provided novel insight into the anticancer effects of Resv and revealed that targeting the SIRT3/AMPK/autophagy pathway can serve as a new therapeutic target against breast cancer.