BMP7 promotes cisplatin chemoresistance of cervical cancer cells through the PI3K/AKT signaling pathway

Abstract

Chemotherapy with cisplatin is one of the standard treatments for patients with advanced or recurrent cervical cancer (CC). However, chemoresistance can develop, compromising its efficacy in clinical practice. We previously observed an indirect role of bone morphogenetic protein 7 (BMP7) in cisplatin chemoresistance and in processes associated with cell plasticity in CC by acting on endothelial cells. In this work, the objective was to investigate a direct role of BMP7 in chemoresistance to cisplatin in CC and the molecular mechanisms involved. First, we evaluated the viability of both control HeLa cells and HeLa cells overexpressing BMP7, obtained via CRISPR/dCas9 technology, when exposed to different concentrations of cisplatin using the neutral red assay. Compared to control cells, BMP7-overexpressing HeLa cells exhibited higher viability under increasing concentrations of cisplatin and a higher half-maximal inhibitory concentration (IC50) of cisplatin. These results were confirmed by trypan blue dye exclusion testing. Then, we investigated the impact of this cytokine on markers involved in apoptosis and cell cycle regulation modulated by cisplatin using Western Blot analysis. We found that overexpression of BMP7 reverses the PARP cleavage, the decrease in cyclin D1 expression, and the Akt phosphorylation induced by cisplatin in CC cells. An increase in Akt phosphorylation levels was further observed in BMP7-overexpressing cells. Finally, we employed a trypan blue assay to determine the effect of LY294002, a phosphatidylinositol-3-kinase (PI3K) inhibitor, which is a key enzyme involved in the activation of Akt, on the cell viability of CC cells. LY294002 reversed the increase in cell viability induced by BMP7 under cisplatin treatment. Taken together, these results provide evidence that BMP7 plays a significant role in cisplatin resistance in cervical cancer cells by influencing the PI3K/Akt pathway.