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Tumor Biology |
Department of Biochemistry and Molecular Biology [Y. G., N. K.], Division of Urology [N. K.], and the Cancer Center [N. K.], University of Maryland School of Medicine, Baltimore, Maryland 21201
ABSTRACT
Previous studies (Y. Guo and N. Kyprianou, Cell Growth Diff., 9: 185–193, 1998) have demonstrated that overexpression of transforming growth factor (TGF) ß type II receptor (TßRII) gene in human prostate cancer cells LNCaP, which are refractory to TGF-ß1 and lack TßRII receptor expression, can restore TGF-ß1 sensitivity and suppress in vitro tumorigenic growth by inhibiting cell proliferation. In the present study, we investigated the effect of TßRII receptor overexpression in LNCaP cells on apoptosis induction and tumorigenicity. The ability of LNCaP cells that overexpress TßRII to undergo apoptosis in response to TGF-ß1 was examined by DNA fragmentation and terminal transferase-mediated dUTP-biotin end labeling analysis. To explore the potential apoptotic nature of TGF-ß1-mediated antitumor effect against human prostate cancer cells, the expression of apoptotic proteins bcl-2 and bax was examined by Western blot analyses. The significance of caspase 1 in TGF-ß1-mediated apoptosis was also determined by examining the expression and activation of caspase 1 by reverse transcription-PCR and Western blot analyses, respectively. Comparative analysis of tumorigenicity of the parental LNCaP and TßRII-overexpressing clones in severely combined immunodeficient mice revealed a significant suppression of tumor growth in TßRII transfectant clones compared with parental LNCaP cells and neomycin-control clones (P < 0.05). A significantly higher incidence of endogenous apoptosis was observed in TßRII clone-61-derived tumor compared with the parental LNCaP tumors. This induction of apoptosis in the LNCaP tumors with restored TGF-ß1 signaling was associated with decreased bcl-2 expression, increased bax, and caspase-1 immunoreactivty. Moreover, an increased expression of the cyclin-dependent kinase inhibitor p27Kip1 was detected in TßRII-overexpressing tumors compared with the parental tumors. LNCaP TßRII transfectant cells exhibited a marked induction of apoptosis, paralleled with a decreased bcl-2 expression in response to TGF-ß1 treatment in vitro. This TGF-ß1-mediated apoptosis induction in TßRII transfectant cells was significantly protected by the caspase-1 inhibitor (zVAD-fmk) in a dose-dependent manner. Furthermore, a significant temporal induction of caspase-1 mRNA and protein expression was detected in TßRII cells in response to TGF-ß1 treatment. Our findings suggest that restoration of TGF-ß1 signaling suppresses tumorigenicity of human prostate cancer cells by inducing apoptosis, potentially via a caspase-1-mediated pathway.
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