Anticancer Effects and Molecular Mechanisms of Apigenin in Cervical Cancer Cells

Ya-Hui Chen; Jyun-Xue Wu; Shun-Fa Yang; Chueh-Ko Yang; Tze-Ho Chen; Yi-Hsuan Hsiao

doi:10.3390/cancers14071824

Anticancer Effects and Molecular Mechanisms of Apigenin in Cervical Cancer Cells

Cancers (Basel). 2022 Apr 4;14(7):1824. doi: 10.3390/cancers14071824.

Authors

Ya-Hui Chen^{1

2}, Jyun-Xue Wu¹, Shun-Fa Yang^{2

3}, Chueh-Ko Yang¹, Tze-Ho Chen⁴, Yi-Hsuan Hsiao^{1

2

4

5

6

7}

Affiliations

¹ Women's Health Research Laboratory, Changhua Christian Hospital, Changhua 50006, Taiwan.
² Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
³ Department of Medical Research, Chung Shan Medical University Hospital, Taichung 40201, Taiwan.
⁴ Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua 50006, Taiwan.
⁵ School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan.
⁶ College of Medicine, Kaohsiung Medical University, Kaohsiung 807378, Taiwan.
⁷ Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan.

Abstract

Cervical cancer is the fourth most frequent malignancy in women. Apigenin is a natural plant-derived flavonoid present in common fruit, vegetables, and herbs, and has been found to possess antioxidant and anti-inflammatory properties as a health-promoting agent. It also exhibits important anticancer effects in various cancers, but its effects are not widely accepted by clinical practitioners. The present study investigated the anticancer effects and molecular mechanisms of apigenin in cervical cancer in vitro and in vivo. HeLa and C33A cells were treated with different concentrations of apigenin. The effects of apigenin on cell viability, cell cycle distribution, migration potential, phosphorylation of PI3K/AKT, the integrin β1-FAK signaling pathway, and epithelial-to-mesenchymal transition (EMT)-related protein levels were investigated. Mechanisms identified from the in vitro study were further validated in a cervical tumor xenograft mouse model. Apigenin effectively inhibited the growth of cervical cancer cells and cervical tumors in xenograft mice. Furthermore, the apigenin down-regulated FAK signaling (FAK, paxillin, and integrin β1) and PI3K/AKT signaling (PI3K, AKT, and mTOR), inactivated or activated various signaling targets, such as Bcl-2, Bax, p21^cip1, CDK1, CDC25c, cyclin B1, fibronectin, N-cadherin, vimentin, laminin, and E-cadherin, promoted mitochondrial-mediated apoptosis, induced G2/M-phase cell cycle arrest, and reduced EMT to inhibit HeLa and C33A cancer cell migration, producing anticancer effects in cervical cancer. Thus, apigenin may act as a chemotherapeutic agent for cervical cancer treatment.

Keywords: EMT; PI3K/AKT; apigenin; apoptosis; cervical cancer; integrin β1-FAK.