Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth
- Autores
- Wan, Xinhai; Li, Zhi-Gang; Yingling, Jonathan M.; Yang, Jun; Starbuck, Michael W.; Ravoori, Murali K.; Kundra, Vikas; Vazquez, Elba Susana; Navone, Nora
- Año de publicación
- 2012
- Idioma
- inglés
- Tipo de recurso
- artículo
- Estado
- versión publicada
- Descripción
- Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo, the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with X-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro. As expected, LY2109761 reversed the TGF-β1-induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo, LY2109761 treatment for 6. weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice (p<0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor-bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth in bone. Thus, targeting TGF-β receptor I is a valuable intervention in men with advanced PCa.
Fil: Wan, Xinhai. University of Texas; Estados Unidos
Fil: Li, Zhi-Gang. University of Texas; Estados Unidos
Fil: Yingling, Jonathan M.. Eli Lilly And Company; Estados Unidos
Fil: Yang, Jun. University of Texas; Estados Unidos
Fil: Starbuck, Michael W.. University of Texas; Estados Unidos
Fil: Ravoori, Murali K.. University of Texas; Estados Unidos
Fil: Kundra, Vikas. University of Texas; Estados Unidos
Fil: Vazquez, Elba Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina
Fil: Navone, Nora. University of Texas; Estados Unidos - Materia
-
BONE METASTASES
PROSTATE CANCER
TGF-Β
TGF-Β RECEPTOR TYPE I KINASE INHIBITOR - Nivel de accesibilidad
- acceso abierto
- Condiciones de uso
- https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
- Repositorio
- Institución
- Consejo Nacional de Investigaciones Científicas y Técnicas
- OAI Identificador
- oai:ri.conicet.gov.ar:11336/95879
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Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growthWan, XinhaiLi, Zhi-GangYingling, Jonathan M.Yang, JunStarbuck, Michael W.Ravoori, Murali K.Kundra, VikasVazquez, Elba SusanaNavone, NoraBONE METASTASESPROSTATE CANCERTGF-ΒTGF-Β RECEPTOR TYPE I KINASE INHIBITORhttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo, the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with X-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro. As expected, LY2109761 reversed the TGF-β1-induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo, LY2109761 treatment for 6. weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice (p<0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor-bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth in bone. Thus, targeting TGF-β receptor I is a valuable intervention in men with advanced PCa.Fil: Wan, Xinhai. University of Texas; Estados UnidosFil: Li, Zhi-Gang. University of Texas; Estados UnidosFil: Yingling, Jonathan M.. Eli Lilly And Company; Estados UnidosFil: Yang, Jun. University of Texas; Estados UnidosFil: Starbuck, Michael W.. University of Texas; Estados UnidosFil: Ravoori, Murali K.. University of Texas; Estados UnidosFil: Kundra, Vikas. University of Texas; Estados UnidosFil: Vazquez, Elba Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; ArgentinaFil: Navone, Nora. University of Texas; Estados UnidosElsevier Science Inc2012-03info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/95879Wan, Xinhai; Li, Zhi-Gang; Yingling, Jonathan M.; Yang, Jun; Starbuck, Michael W.; et al.; Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth; Elsevier Science Inc; Bone; 50; 3; 3-2012; 695-7038756-3282CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S8756328211013615info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bone.2011.11.022info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T09:45:13Zoai:ri.conicet.gov.ar:11336/95879instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 09:45:14.274CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse |
dc.title.none.fl_str_mv |
Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth |
title |
Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth |
spellingShingle |
Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth Wan, Xinhai BONE METASTASES PROSTATE CANCER TGF-Β TGF-Β RECEPTOR TYPE I KINASE INHIBITOR |
title_short |
Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth |
title_full |
Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth |
title_fullStr |
Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth |
title_full_unstemmed |
Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth |
title_sort |
Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth |
dc.creator.none.fl_str_mv |
Wan, Xinhai Li, Zhi-Gang Yingling, Jonathan M. Yang, Jun Starbuck, Michael W. Ravoori, Murali K. Kundra, Vikas Vazquez, Elba Susana Navone, Nora |
author |
Wan, Xinhai |
author_facet |
Wan, Xinhai Li, Zhi-Gang Yingling, Jonathan M. Yang, Jun Starbuck, Michael W. Ravoori, Murali K. Kundra, Vikas Vazquez, Elba Susana Navone, Nora |
author_role |
author |
author2 |
Li, Zhi-Gang Yingling, Jonathan M. Yang, Jun Starbuck, Michael W. Ravoori, Murali K. Kundra, Vikas Vazquez, Elba Susana Navone, Nora |
author2_role |
author author author author author author author author |
dc.subject.none.fl_str_mv |
BONE METASTASES PROSTATE CANCER TGF-Β TGF-Β RECEPTOR TYPE I KINASE INHIBITOR |
topic |
BONE METASTASES PROSTATE CANCER TGF-Β TGF-Β RECEPTOR TYPE I KINASE INHIBITOR |
purl_subject.fl_str_mv |
https://purl.org/becyt/ford/3.2 https://purl.org/becyt/ford/3 |
dc.description.none.fl_txt_mv |
Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo, the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with X-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro. As expected, LY2109761 reversed the TGF-β1-induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo, LY2109761 treatment for 6. weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice (p<0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor-bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth in bone. Thus, targeting TGF-β receptor I is a valuable intervention in men with advanced PCa. Fil: Wan, Xinhai. University of Texas; Estados Unidos Fil: Li, Zhi-Gang. University of Texas; Estados Unidos Fil: Yingling, Jonathan M.. Eli Lilly And Company; Estados Unidos Fil: Yang, Jun. University of Texas; Estados Unidos Fil: Starbuck, Michael W.. University of Texas; Estados Unidos Fil: Ravoori, Murali K.. University of Texas; Estados Unidos Fil: Kundra, Vikas. University of Texas; Estados Unidos Fil: Vazquez, Elba Susana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Química Biológica de la Facultad de Ciencias Exactas y Naturales; Argentina Fil: Navone, Nora. University of Texas; Estados Unidos |
description |
Transforming growth factor beta 1 (TGF-β1) has been implicated in the pathogenesis of prostate cancer (PCa) bone metastasis. In this study, we tested the antitumor efficacy of a selective TGF-β receptor I kinase inhibitor, LY2109761, in preclinical models. The effect of LY2109761 on the growth of MDA PCa 2b and PC-3 human PCa cells and primary mouse osteoblasts (PMOs) was assessed in vitro by measuring radiolabeled thymidine incorporation into DNA. In vivo, the right femurs of male SCID mice were injected with PCa cells. We monitored the tumor burden in control- and LY2109761-treated mice with MRI analysis and the PCa-induced bone response with X-ray and micro-CT analyses. Histologic changes in bone were studied by performing bone histomorphometric evaluations. PCa cells and PMOs expressed TGF-β receptor I. TGF-β1 induced pathway activation (as assessed by induced expression of p-Smad2) and inhibited cell growth in PC-3 cells and PMOs but not in MDA PCa 2b cells. LY2109761 had no effect on PCa cells but induced PMO proliferation in vitro. As expected, LY2109761 reversed the TGF-β1-induced pathway activation and growth inhibition in PC-3 cells and PMOs. In vivo, LY2109761 treatment for 6. weeks resulted in increased volume in normal bone and increased osteoblast and osteoclast parameters. In addition, LY2109761 treatment significantly inhibited the growth of MDA PCa 2b and PC-3 in the bone of SCID mice (p<0.05); moreover, it resulted in significantly less bone loss and change in osteoclast-associated parameters in the PC-3 tumor-bearing bones than in the untreated mice. In summary, we report for the first time that targeting TGF-β receptors with LY2109761 can control PCa bone growth while increasing the mass of normal bone. This increased bone mass in nontumorous bone may be a desirable side effect of LY2109761 treatment for men with osteopenia or osteoporosis secondary to androgen-ablation therapy, reinforcing the benefit of effectively controlling PCa growth in bone. Thus, targeting TGF-β receptor I is a valuable intervention in men with advanced PCa. |
publishDate |
2012 |
dc.date.none.fl_str_mv |
2012-03 |
dc.type.none.fl_str_mv |
info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion http://purl.org/coar/resource_type/c_6501 info:ar-repo/semantics/articulo |
format |
article |
status_str |
publishedVersion |
dc.identifier.none.fl_str_mv |
http://hdl.handle.net/11336/95879 Wan, Xinhai; Li, Zhi-Gang; Yingling, Jonathan M.; Yang, Jun; Starbuck, Michael W.; et al.; Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth; Elsevier Science Inc; Bone; 50; 3; 3-2012; 695-703 8756-3282 CONICET Digital CONICET |
url |
http://hdl.handle.net/11336/95879 |
identifier_str_mv |
Wan, Xinhai; Li, Zhi-Gang; Yingling, Jonathan M.; Yang, Jun; Starbuck, Michael W.; et al.; Effect of transforming growth factor beta (TGF-β) receptor I kinase inhibitor on prostate cancer bone growth; Elsevier Science Inc; Bone; 50; 3; 3-2012; 695-703 8756-3282 CONICET Digital CONICET |
dc.language.none.fl_str_mv |
eng |
language |
eng |
dc.relation.none.fl_str_mv |
info:eu-repo/semantics/altIdentifier/url/https://www.sciencedirect.com/science/article/pii/S8756328211013615 info:eu-repo/semantics/altIdentifier/doi/10.1016/j.bone.2011.11.022 |
dc.rights.none.fl_str_mv |
info:eu-repo/semantics/openAccess https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
eu_rights_str_mv |
openAccess |
rights_invalid_str_mv |
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/ |
dc.format.none.fl_str_mv |
application/pdf application/pdf application/pdf |
dc.publisher.none.fl_str_mv |
Elsevier Science Inc |
publisher.none.fl_str_mv |
Elsevier Science Inc |
dc.source.none.fl_str_mv |
reponame:CONICET Digital (CONICET) instname:Consejo Nacional de Investigaciones Científicas y Técnicas |
reponame_str |
CONICET Digital (CONICET) |
collection |
CONICET Digital (CONICET) |
instname_str |
Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.name.fl_str_mv |
CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas |
repository.mail.fl_str_mv |
dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar |
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1844613421275807744 |
score |
13.070432 |