Nimotuzumab inhibits epithelial-mesenchymal transition in prostate cancer by targeting the Akt/YB-1/AR axis.

Abstract

Nimotuzumab is a humanized anti-EGF monoclonal antibody that has been approved for treating different cancers. However, few studies have examined its therapeutic potential in prostate cancer (PC), a most common and highly aggressive malignancy among male population. We used both LNCaP, and PC3 and PC3-AR (androgen receptor) cells as the model system and assessed the effects of nimotuzumab on epithelial-mesenchymal transition (EMT) in vitro and in vivo. The EMT makers were detected by immunohistochemistry, qRT-PCR and Western blot. MTT, wound healing assay, and transwell assay were used to measure cell viability, migration, and invasion, respectively. For mechanistic understanding, we evaluated the significance of Akt/Y-box binding protein-1 (YB-1)/AR axis in nimotuzumab-induced EMT by overexpressing AR, activating Akt using SC79, and/or downregulating YB-1 using siRNA. Nimotuzumab suppressed the xenograft growth from both LNCaP and PC3 cells in vivo, which was associated with reduced EMT. Consistently, nimotuzumab inhibited proliferation, cell-cycle progression, EMT, and migration/invasion, but stimulated apoptosis of both LNCaP and PC3-AR cells in vitro. On the molecular level, nimotuzumab inactivated Akt and YB-1 and reduced the expression of AR. Boosting AR expression in LNCaP and PC3-AR cells antagonized the action of nimotuzumab, at least partially restored EMT, and enhanced the migration/invasion. We also found that Akt was essential for controlling YB-1 activation, and both critical for regulating the levels of AR and EMT-related biomarkers. In this study, we presented our novel findings that by targeting the Akt/YB-1/AR axis, nimotuzumab significantly inhibited EMT of PC cells. Considering that EMT is a critical mechanism contributing to the metastatic spread of cancer cells, nimotuzumab may become a promising therapy for alleviating the malignant progression of PC. © 2019 IUBMB Life, 1-14, 2019.