Recombinant bone morphogenetic protein-2 attenuates colorectal cancer progression by orchestrating Hippo pathway...

Bone morphogenetic protein-2 (BMP-2) regulates cell differentiation and proliferation. However, its role in colorectal cancer (CRC) remains debatable owing to potential oncogenic effects. Here, we investigated the role of BMP-2 in modulating CRC progression, particularly in regulating the Hippo signaling pathway. Exposure to recombinant human BMP-2 (rhBMP-2) resulted in a concentration-dependent decrease in CRC cell proliferation, leading to G1 cell cycle arrest. This effect was associated with the increased expression of p53, p21, and Smad4, while the levels of cyclin D1, cyclin-dependent kinase 4 (CDK4), and CDK6 decreased. Additionally, rhBMP-2 promoted apoptosis by decreasing poly (ADP-ribose) polymerase and caspase-9 expression while increasing their cleaved forms. It also activated the Hippo signaling cascade, enhancing the expression of mammalian sterile 20-like kinase 1/2, Mps One Binder 1 (MOB1), phosphorylated MOB1, and Salvador homolog, along with elevated levels of phosphorylated yes-associated protein (YAP), while concurrently suppressing total YAP expression. This resulted in cytoplasmic sequestration and subsequent degradation of YAP, thereby attenuating the transcription of YAP-responsive genes such as Connective Tissue Growth Factor. Silencing of Ras association domain family member 1 restored the rhBMP-2-induced decrease in cell viability, whereas silencing YAP further reduced the viability of CRC cell lines. Administering rhBMP-2 significantly suppressed tumor expansion in a mouse model of CRC, further supporting its potential as an antitumor agent. Collectively, these results indicate that rhBMP-2 mitigates CRC progression by activating the Hippo signaling pathway and suppressing YAP-mediated oncogenic processes, thereby highlighting its potential as a therapeutic agent that warrants further clinical evaluation.