Bevacizumab increases cisplatin efficacy by inhibiting epithelial-mesenchymal transition via ALDH1 in cervical carcinoma.

Abstract

Cervical carcinoma has the highest incidence among gynaecological cancers in developing countries where the human papillomavirus (HPV) vaccine is not yet widely used. Cancer stem cells (CSCs) are the key factors affecting treatment efficacy and cancer prognosis. Aldehyde dehydrogenase 1 (ALDH1) is a marker of CSCs, and its expression is closely related to chemotherapy resistance in cervical carcinoma. Bevacizumab is the most widely used molecular targeted drug in the management of cervical carcinoma. We designed and performed a series of in vitro and in vivo experiments to investigate the inhibitory effects of these compounds on ALDH1 and the underlying mechanism involved. The results revealed that bevacizumab significantly inhibited epithelial-mesenchymal transition (EMT) in HeLa cervical cancer cells, as indicated by upregulation of E-cadherin and downregulation of N-cadherin and snail. Anoxic pressure was relieved, and tumour vascularization was inhibited in the tumour microenvironment. NOTCH1 plays a critical role in these processes. Through modulating these tumour biological characteristics via ALDH1, bevacizumab increases the sensitivity of cervical carcinoma to cisplatin, suggesting that bevacizumab in combination with standard chemotherapy may represent a new strategy for overcoming drug resistance. Abbreviation: HPV, human papillomavirus; CSCs, cancer stem cells; ALDH1, aldehyde dehydrogenase 1; EMT, epithelial-mesenchymal transition; OD, optical density; qRT-PCR, RNA analysis by quantitative real-time polymerase chain reaction; RIPA, radioimmunoprecipitation assay; SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis; PVDF, polyvinylidene difluoride; ECL, electrochemiluminescence; NC, negative control; HE, haematoxylin and eosin; IHC, immunohistochemistry; DAB, 3, 3'-diaminobenzidine; IF, immunofluorescence; DAPI, 4,6-diamidino-2-phenylindole; VEGFA, vascular endothelial growth factor A; ROS, oxygen species; DFS, disease-free survival; OS, overall survival; HIF, hypoxia-inducible factor; PDGFs, platelet-derived growth factors; FGFs, fibroblast growth factors; PlGF, placenta growth factor; RTKs, receptor tyrosine kinases.