Gelsolin Governs the Neuroendocrine Transdifferentiation of Prostate Cancer Cells and Suppresses the Apoptotic Machinery.

Abstract

Interleukin 6 (IL6) is increased in patients with progressive prostate cancer and induces its transdifferentiation to neuroendocrine prostate cancer. Neuroendocrine prostate cancer has become one of the greatest challenges in treating castration-resistant disease and is linked to poor prognosis. It is necessary to understand better the cellular events associated with IL6-mediated neuroendocrine differentiation to prevent it and identify potential new therapeutic targets. In the present study, an IL6-inducible neuroendocrine differentiation model established specifically for this purpose was applied using LNCaP cells. Proteomics and western blot analyses were used to identify proteins involved in neuroendocrine differentiation. Subsequently, the role of gelsolin (GSN) in the neuroendocrine differentiation model was characterized (knock-down analyses, microscopic co-localization analyses, apoptosis assay) and GSN expression levels in patient material were investigated. This study revealed that GSN is a crucial factor in the neuroendocrine differentiation process. It was shown that siRNA-mediated knock-down of GSN can inhibit neuroendocrine differentiation, making it a valid target for preventing IL6-mediated neuroendocrine differentiation.