Prohibitin and cofilin are intracellular effectors of transforming growth factor β signaling in human prostate cancer cells

Abstract

A proteomic analysis was pursued to identify new signaling effectors of transforming growth factor β1 (TGF-β1) that serve as potential intracellular effectors of its apoptotic action in human prostate cancer cells. The androgen-sensitive and TGF-β-responsive human prostate cancer cells, LNCaP TβRII, were used as in vitro model. In response to TGF-β, significant post-translational changes in two proteins temporally preceded apoptotic cell death. TGF-β mediated the nuclear export of prohibitin, a protein involved in androgen-regulated prostate growth, to the cytosol in the LNCaP TβRII cells. Cofilin, a protein involved in actin depolymerization, cell motility, and apoptosis, was found to undergo mitochondrial translocation in response to TGF-β before cytochrome c release. Loss-of-function approaches (small interfering RNA) to silence prohibitin expression revealed a modest decrease in the apoptotic response to TGF-β and a significant suppression in TGF-β-induced cell migration. Silencing Smad4 showed that the cellular localization changes associated with prohibitin and cofilin action in response to TGF-β are independent of Smad4 intracellular signaling. ©2006 American Association for Cancer Research.