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Restoration of transforming growth factor beta signaling pathway in human prostate cancer cells suppresses tumorigenicity via induction of caspase-1-mediated apoptosis.
Cancer Res 1999; 59(6):1366-71CR

Abstract

Previous studies (Y. Guo and N. Kyprianou, Cell Growth Diff., 9: 185-193, 1998) have demonstrated that overexpression of transforming growth factor (TGF) beta type II receptor (TbetaRII) gene in human prostate cancer cells LNCaP, which are refractory to TGF-beta1 and lack TbetaRII receptor expression, can restore TGF-beta1 sensitivity and suppress in vitro tumorigenic growth by inhibiting cell proliferation. In the present study, we investigated the effect of TbetaRII receptor overexpression in LNCaP cells on apoptosis induction and tumorigenicity. The ability of LNCaP cells that overexpress TbetaRII to undergo apoptosis in response to TGF-beta1 was examined by DNA fragmentation and terminal transferase-mediated dUTP-biotin end labeling analysis. To explore the potential apoptotic nature of TGF-beta1-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-beta1-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 TbetaRII-overexpressing clones in severely combined immunodeficient mice revealed a significant suppression of tumor growth in TbetaRII transfectant clones compared with parental LNCaP cells and neomycin-control clones (P < 0.05). A significantly higher incidence of endogenous apoptosis was observed in TbetaRII clone-61-derived tumor compared with the parental LNCaP tumors. This induction of apoptosis in the LNCaP tumors with restored TGF-beta1 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 TbetaRII-overexpressing tumors compared with the parental tumors. LNCaP TbetaRII transfectant cells exhibited a marked induction of apoptosis, paralleled with a decreased bcl-2 expression in response to TGF-beta1 treatment in vitro. This TGF-beta1-mediated apoptosis induction in TbetaRII 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 TbetaRII cells in response to TGF-beta1 treatment. Our findings suggest that restoration of TGF-beta1 signaling suppresses tumorigenicity of human prostate cancer cells by inducing apoptosis, potentially via a caspase-1-mediated pathway.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore 21201, USA.No affiliation info available

Pub Type(s)

Journal Article
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

10096572

Citation

Guo, Y, and N Kyprianou. "Restoration of Transforming Growth Factor Beta Signaling Pathway in Human Prostate Cancer Cells Suppresses Tumorigenicity Via Induction of Caspase-1-mediated Apoptosis." Cancer Research, vol. 59, no. 6, 1999, pp. 1366-71.
Guo Y, Kyprianou N. Restoration of transforming growth factor beta signaling pathway in human prostate cancer cells suppresses tumorigenicity via induction of caspase-1-mediated apoptosis. Cancer Res. 1999;59(6):1366-71.
Guo, Y., & Kyprianou, N. (1999). Restoration of transforming growth factor beta signaling pathway in human prostate cancer cells suppresses tumorigenicity via induction of caspase-1-mediated apoptosis. Cancer Research, 59(6), pp. 1366-71.
Guo Y, Kyprianou N. Restoration of Transforming Growth Factor Beta Signaling Pathway in Human Prostate Cancer Cells Suppresses Tumorigenicity Via Induction of Caspase-1-mediated Apoptosis. Cancer Res. 1999 Mar 15;59(6):1366-71. PubMed PMID: 10096572.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Restoration of transforming growth factor beta signaling pathway in human prostate cancer cells suppresses tumorigenicity via induction of caspase-1-mediated apoptosis. AU - Guo,Y, AU - Kyprianou,N, PY - 1999/3/30/pubmed PY - 1999/3/30/medline PY - 1999/3/30/entrez SP - 1366 EP - 71 JF - Cancer research JO - Cancer Res. VL - 59 IS - 6 N2 - Previous studies (Y. Guo and N. Kyprianou, Cell Growth Diff., 9: 185-193, 1998) have demonstrated that overexpression of transforming growth factor (TGF) beta type II receptor (TbetaRII) gene in human prostate cancer cells LNCaP, which are refractory to TGF-beta1 and lack TbetaRII receptor expression, can restore TGF-beta1 sensitivity and suppress in vitro tumorigenic growth by inhibiting cell proliferation. In the present study, we investigated the effect of TbetaRII receptor overexpression in LNCaP cells on apoptosis induction and tumorigenicity. The ability of LNCaP cells that overexpress TbetaRII to undergo apoptosis in response to TGF-beta1 was examined by DNA fragmentation and terminal transferase-mediated dUTP-biotin end labeling analysis. To explore the potential apoptotic nature of TGF-beta1-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-beta1-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 TbetaRII-overexpressing clones in severely combined immunodeficient mice revealed a significant suppression of tumor growth in TbetaRII transfectant clones compared with parental LNCaP cells and neomycin-control clones (P < 0.05). A significantly higher incidence of endogenous apoptosis was observed in TbetaRII clone-61-derived tumor compared with the parental LNCaP tumors. This induction of apoptosis in the LNCaP tumors with restored TGF-beta1 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 TbetaRII-overexpressing tumors compared with the parental tumors. LNCaP TbetaRII transfectant cells exhibited a marked induction of apoptosis, paralleled with a decreased bcl-2 expression in response to TGF-beta1 treatment in vitro. This TGF-beta1-mediated apoptosis induction in TbetaRII 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 TbetaRII cells in response to TGF-beta1 treatment. Our findings suggest that restoration of TGF-beta1 signaling suppresses tumorigenicity of human prostate cancer cells by inducing apoptosis, potentially via a caspase-1-mediated pathway. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/10096572/Restoration_of_transforming_growth_factor_beta_signaling_pathway_in_human_prostate_cancer_cells_suppresses_tumorigenicity_via_induction_of_caspase_1_mediated_apoptosis_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&amp;pmid=10096572 DB - PRIME DP - Unbound Medicine ER -