Targeting TUBB3 Suppresses Anoikis Resistance and Bone Metastasis in Prostate Cancer.

1. Adv Healthc Mater. 2024 Nov;13(28):e2400673. doi: 10.1002/adhm.202400673. Epub 2024 Jun 6. Targeting TUBB3 Suppresses Anoikis Resistance and Bone Metastasis in Prostate Cancer. Dong B(1), Gu Y(2)(3)(4), Sun X(4)(5), Wang X(1), Zhou Y(3), Rong Z(3), Zhang J(6), Shi X(7), Zhang Z(3), He X(2)(4), Chen L(2)(3)(4), Xiong Q(8), Pang X(2)(3), Cui Y(2)(4). Author information: (1)Department of General Surgery, Peking University First Hospital, Xishiku Street, Xicheng District, Beijing, 100034, China. (2)Institute of Clinical Pharmacology, Peking University First Hospital, Xueyuan Road 38, Haidian District, Beijing, 100191, China. (3)Department of Pharmacy, Peking University First Hospital, Xishiku Street, Xicheng District, Beijing, 100034, China. (4)School of Pharmaceutical Sciences, Peking University, Xueyuan Road 38, Haidian District, Beijing, 100191, China. (5)Department of Urology Surgery, Peking University Third Hospital, Xueyuan Road 38, Haidian District, Beijing, 100191, China. (6)Department of Pathology, Peking University First Hospital, Xishiku Street, Xicheng District, Beijing, 100034, China. (7)Department of Orthopedics, Peking University First Hospital, Xishiku Street, Xicheng District, Beijing, 100034, China. (8)Department of Hepatobiliary Cancer, Liver Cancer Center, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin Key Laboratory of Digestive Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, Tianjin's Clinical Research Center for Cancer, Tianjin, 300060, P. R. China. Bone 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. © 2024 The Author(s). Advanced Healthcare Materials published by Wiley‐VCH GmbH. DOI: 10.1002/adhm.202400673 PMID: 38809199 [Indexed for MEDLINE]