Apigenin is an anoikis sensitizer with strong anti-metastatic properties in experimental breast cancer
Ruijie Xu, Zhijie Yao, Hao Zhang, Haitao Li, Wei Chen
Abstract
Loss of susceptibility to anoikis signals is a crucial step in metastasis. Anoikis resistance therefore represents a promising adjuvant therapeutic target for cancer management. In this study, we have conducted a rationalized screening to search for novel leading anoikis<strong> </strong>sensitizer from daily foods. Among 19 tested dietary phytochemicals, the best results were obtained with apigenin, a natural component of celery. Phenotypically, apigenin sensitized breast cancer cells to anoikis,<em> </em>lowered the number of circulating tumor cells, and protected against breast cancer metastasis to lung in mice. Mechanistically, we demonstrated that the thromboxane A<sub>2</sub> (TXA<sub>2</sub>)- TXA<sub>2</sub> receptor (TP) axis has a critical role in acquired anoikis resistance by activating PI3K-Akt signaling pathway. Blockage of TXA<sub>2</sub> signaling up-regulate p53 as well as its target gene p21, caused a G1 phase arrest, and finally led to apoptosis in breast cancer cells. TXA<sub>2</sub> level was positively correlated with breast cancer cell anoikis rate, and apigenin significantly inhibited TXA<sub>2</sub> biosynthesis <em>in vitro</em> and <em>in vivo.</em> Collectively, we identified apigenin as potent anoikis<strong> </strong>sensitizer with anti-metastatic properties in a mouse model of breast cancer, and these findings might provide a rationale for introducing apigenin supplementation to breast cancer patients.