Induction of entosis in prostate cancer cells by nintedanib and its therapeutic implications

Entosis is a homogeneous cell-in-cell phenomenon and a non-apoptotic cell death process. Tyrosine kinase inhibitors have been used in the treatment of prostate cancer and have already demonstrated efficacy in a clinical setting. The present study investigated the role of entosis in prostate cancer treated with the tyrosine kinase inhibitor nintedanib. Prostate cancer cells were treated with nintedanib in vitro and entosis was observed. Mice xenografts were created to evaluate whether nintedanib is able to induce entosis in vivo. The reverse transcription-quantitative polymerase chain reaction, western blotting and immunofluorescence were performed to investigate whether the entosis pathway is induced by nintedanib. It was also investigated whether entosis can contribute to cell survival and progression under nintedanib stress, and nintedanib was revealed to enhance prostate cancer cell entosis. Nintedanib-induced entosis in prostate cancer cells occurred through phosphoinositide 3-kinase/cell division cycle 42 (CDC42) inhibition, followed by the upregulation of epithelial (E-)cadherin and components of the Rho kinase (ROCK) signaling pathway. In addition, nintedanib-resistant cells exhibiting entosis had a higher invasive ability. In addition, in vivo treatment of mice xenografts with nintedanib also increased the expression of E-cadherin and components of the ROCK signaling pathway. Nintedanib can promote entosis during prostate cancer treatment by modulating the CDC42 pathway. Furthermore, prostate cancer cells acquired nintedanib resistance and survived by activating entosis.