Significance of transforming growth factor-beta1-mediated signaling pathways in human prostate tumorigenesis

Abstract

Transforming growth factor-beta (TGF-beta1) is a potent growth inhibitor that interacts with type I and II receptors. To investigate whether deregulation of TGF-beta receptors is involved in human prostate tumor progression, the expression of receptors at the protein and mRNA level, was examined in tissue specimens from a series of human primary and metastatic prostate tumor and normal prostate. Decreased expression of both TGF-beta1 type I and II receptors was found in primary and metastatic prostatic tumors compared to normal prostate and BPH (benign prostatic hyperplasia). The human prostate cancer cells, LNCaP, which are refractory to TGF-beta1 and lack TbetaRII receptor, were transfected with wild type TbetaRII. The TGF-beta1-mediated growth inhibition and tumorigenicity in vitro and in vivo were examined in the TbetaRII transfectant clones. Restoration to TGF-beta1 sensitivity and suppression of tumorigenicity were detected in LNCaP TbetaRII cells. The effect of TGF-beta1 on cyclin-dependent kinase inhibitors and cell cycle progression was also investigated. TbetaRII overexpressing clones showed a significant induction of p21 WAF1, p27Kip1, and p15INK4B, and G1 arrest by exogenous TGF-beta1. The possibility that TGF-beta1 induces apoptosis in LNCaP cells was also studied. A significant induction of apoptosis by exogenous TGF-beta1 was detected in TbetaRII overexpressing clones. Furthermore, the involvement of apoptotic proteins, bcl-2 and bax, and caspase-1 was studied. Significant induction of apoptosis was observed in LNCaP overexpressing TbetaRII with TGF-beta1 treatment. The induction of apoptosis mediated by TGF-beta1 was associated with upregulation of caspase-1, bax, and downregulation of bcl-2. The expression of a potential downstream regulator of TGF-beta1 signaling, p27Kip1 was examined in a series of paraffin-embedded tissue sections from primary and metastatic prostate cancer, as well as benign prostatic hyperplasia (BPH). Downregulation of p27Kip1 was found in prostate tumors compared to normal prostate, and this loss of expression of p27Kip1 correlated with tumor progression.