Targeting TUBB3 Suppresses Anoikis Resistance and Bone Metastasis in Prostate Cancer

Abstract

AbstractBone metastases occur in more than 70% of advanced prostate cancer (PCa) patients, leading to a poor prognosis. Resistance to detachment‐induced apoptosis, also known as anoikis, plays a crucial role in the onset of tumor metastasis. Targeting anoikis resistance is of immense therapeutic significance in repression of metastatic spread. In this study, based on an anoikis‐related prognostic risk model of PCa, this study identifies TUBB3 as a key anoikis‐related prognostic gene that is highly expressed in bone metastatic PCa. TUBB3 expression is increased in anoikis‐resistant PCa cells, and TUBB3 depletion significantly reverses anoikis resistance during extracellular matrix (ECM) detachment and inhibits anoikis‐resistance‐induced PCa cell invasion and migration as well as epithelial‐mesenchymal transition (EMT) process. TUBB3 knockdown significantly reduces αvβ3/FAK/Src axis activation, blocking its downstream oncogenic signaling. In addition, this work develops bone‐targeting lipid nanoparticles (BT‐LNP) based on bisphosphonate‐modified ionizable lipid for systemic delivery of siRNA targeting TUBB3 (siTUBB3). BT‐LNP‐delivered siTUBB3 therapy with localization in the bone microenvironment significantly attenuate PCa bone metastasis progression in vivo upon intravenous administration. These findings pinpoint that TUBB3, as a key regulator of anoikis resistance, is an effective therapeutic target in bone metastatic PCa and that BT‐LNP‐mediated systemic delivery of siTUBB3 can be developed as a novel therapeutic strategy for this disease.