Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell Lines

Autores
Benavent Acero, Fernando Rodrigo; Perera Negrin, Yasser; Alonso, Daniel Fernando; Perea, Silvio E.; Gomez, Daniel Eduardo; Farina, Hernán Gabriel
Año de publicación
2014
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
CIGB-300 is a cyclic synthetic peptide that induces apoptosis in malignant cells, elicits antitumor activity in cancer animal models, and shows tumor reduction signs when assayed in first-in-human phase I trial in patients with cervical tumors. CIGB-300 impairs phosphorylation by casein kinase 2 through targeting the substrate´s phosphoacceptor domain. CIGB-300 was linked to the cell penetrating peptide Tat to facilitate the delivery into cells. Previously, we showed that CIGB-300 had a differential antiproliferative behavior in different tumor cell lines. In this work, we studied differential antiproliferative behavior in terms of cellular uptake, intracellular transportation, and degradation in tumor cell lines with dissimilar sensitivity to CIGB-300. The internalization of CIGB-300 was studied in different malignant cell lines. We found that the cell membrane heparan sulfate proteoglycans act as main receptors for extracellular CIGB-300 uptake. The most sensitive tumor cell lines showed higher intracellular incorporation of CIGB-300 in comparison to less sensitive cell lines. Furthermore, CIGB-300 uptake is time- and concentration-dependent in all studied cell lines. It was shown that CIGB-300 has the ability to penetrate cells mainly by direct membrane translocation. However, a minor proportion of the peptide uses an energy-dependent endocytic pathway mechanism to gain access into cells. CIGB-300 is internalized and transported into cells preferentially by caveolae-mediated endocytosis. Lysosomes are involved in CIGB-300 degradation; highly sensitive cell lines showed degradation at earlier times compared to low sensitive cells. Altogether, our data suggests a mechanism of internalization, vesicular transportation, and degradation for CIGB-300 in tumor cells.
Fil: Benavent Acero, Fernando Rodrigo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Perera Negrin, Yasser. Centro de Ingeniería Genética y Biotecnología. Laboratorio de Oncología Molecular; Cuba
Fil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Perea, Silvio E.. Centro de Ingeniería Genética y Biotecnología. Laboratorio de Oncología Molecular; Cuba
Fil: Gomez, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Farina, Hernán Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Materia
Ck2 Kinase
Cancer
Tat Peptide
Cigb-300
Cpp
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/33738
Acceder
id CONICETDig_4a08e4bec69cc8570df810b12b0b2fd7
oai_identifier_str oai:ri.conicet.gov.ar:11336/33738
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell LinesBenavent Acero, Fernando RodrigoPerera Negrin, YasserAlonso, Daniel FernandoPerea, Silvio E.Gomez, Daniel EduardoFarina, Hernán GabrielCk2 KinaseCancerTat PeptideCigb-300Cpphttps://purl.org/becyt/ford/1.6https://purl.org/becyt/ford/1CIGB-300 is a cyclic synthetic peptide that induces apoptosis in malignant cells, elicits antitumor activity in cancer animal models, and shows tumor reduction signs when assayed in first-in-human phase I trial in patients with cervical tumors. CIGB-300 impairs phosphorylation by casein kinase 2 through targeting the substrate´s phosphoacceptor domain. CIGB-300 was linked to the cell penetrating peptide Tat to facilitate the delivery into cells. Previously, we showed that CIGB-300 had a differential antiproliferative behavior in different tumor cell lines. In this work, we studied differential antiproliferative behavior in terms of cellular uptake, intracellular transportation, and degradation in tumor cell lines with dissimilar sensitivity to CIGB-300. The internalization of CIGB-300 was studied in different malignant cell lines. We found that the cell membrane heparan sulfate proteoglycans act as main receptors for extracellular CIGB-300 uptake. The most sensitive tumor cell lines showed higher intracellular incorporation of CIGB-300 in comparison to less sensitive cell lines. Furthermore, CIGB-300 uptake is time- and concentration-dependent in all studied cell lines. It was shown that CIGB-300 has the ability to penetrate cells mainly by direct membrane translocation. However, a minor proportion of the peptide uses an energy-dependent endocytic pathway mechanism to gain access into cells. CIGB-300 is internalized and transported into cells preferentially by caveolae-mediated endocytosis. Lysosomes are involved in CIGB-300 degradation; highly sensitive cell lines showed degradation at earlier times compared to low sensitive cells. Altogether, our data suggests a mechanism of internalization, vesicular transportation, and degradation for CIGB-300 in tumor cells.Fil: Benavent Acero, Fernando Rodrigo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Perera Negrin, Yasser. Centro de Ingeniería Genética y Biotecnología. Laboratorio de Oncología Molecular; CubaFil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Perea, Silvio E.. Centro de Ingeniería Genética y Biotecnología. Laboratorio de Oncología Molecular; CubaFil: Gomez, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaFil: Farina, Hernán Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; ArgentinaAmerican Chemical Society2014-04info: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/11336/33738Gomez, Daniel Eduardo; Farina, Hernán Gabriel; Benavent Acero, Fernando Rodrigo; Alonso, Daniel Fernando; Perera Negrin, Yasser; Perea, Silvio E.; et al.; Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell Lines; American Chemical Society; Molecular Pharmaceutics; 6; 11; 4-2014; 1798-18071543-8384CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1021/mp4006062info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/mp4006062info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-17T10:54:54Zoai:ri.conicet.gov.ar:11336/33738instacron: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:34982025-09-17 10:54:54.818CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell Lines
title Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell Lines
spellingShingle Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell Lines
Benavent Acero, Fernando Rodrigo
Ck2 Kinase
Cancer
Tat Peptide
Cigb-300
Cpp
title_short Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell Lines
title_full Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell Lines
title_fullStr Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell Lines
title_full_unstemmed Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell Lines
title_sort Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell Lines
dc.creator.none.fl_str_mv Benavent Acero, Fernando Rodrigo
Perera Negrin, Yasser
Alonso, Daniel Fernando
Perea, Silvio E.
Gomez, Daniel Eduardo
Farina, Hernán Gabriel
author Benavent Acero, Fernando Rodrigo
author_facet Benavent Acero, Fernando Rodrigo
Perera Negrin, Yasser
Alonso, Daniel Fernando
Perea, Silvio E.
Gomez, Daniel Eduardo
Farina, Hernán Gabriel
author_role author
author2 Perera Negrin, Yasser
Alonso, Daniel Fernando
Perea, Silvio E.
Gomez, Daniel Eduardo
Farina, Hernán Gabriel
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv Ck2 Kinase
Cancer
Tat Peptide
Cigb-300
Cpp
topic Ck2 Kinase
Cancer
Tat Peptide
Cigb-300
Cpp
purl_subject.fl_str_mv https://purl.org/becyt/ford/1.6
https://purl.org/becyt/ford/1
dc.description.none.fl_txt_mv CIGB-300 is a cyclic synthetic peptide that induces apoptosis in malignant cells, elicits antitumor activity in cancer animal models, and shows tumor reduction signs when assayed in first-in-human phase I trial in patients with cervical tumors. CIGB-300 impairs phosphorylation by casein kinase 2 through targeting the substrate´s phosphoacceptor domain. CIGB-300 was linked to the cell penetrating peptide Tat to facilitate the delivery into cells. Previously, we showed that CIGB-300 had a differential antiproliferative behavior in different tumor cell lines. In this work, we studied differential antiproliferative behavior in terms of cellular uptake, intracellular transportation, and degradation in tumor cell lines with dissimilar sensitivity to CIGB-300. The internalization of CIGB-300 was studied in different malignant cell lines. We found that the cell membrane heparan sulfate proteoglycans act as main receptors for extracellular CIGB-300 uptake. The most sensitive tumor cell lines showed higher intracellular incorporation of CIGB-300 in comparison to less sensitive cell lines. Furthermore, CIGB-300 uptake is time- and concentration-dependent in all studied cell lines. It was shown that CIGB-300 has the ability to penetrate cells mainly by direct membrane translocation. However, a minor proportion of the peptide uses an energy-dependent endocytic pathway mechanism to gain access into cells. CIGB-300 is internalized and transported into cells preferentially by caveolae-mediated endocytosis. Lysosomes are involved in CIGB-300 degradation; highly sensitive cell lines showed degradation at earlier times compared to low sensitive cells. Altogether, our data suggests a mechanism of internalization, vesicular transportation, and degradation for CIGB-300 in tumor cells.
Fil: Benavent Acero, Fernando Rodrigo. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina
Fil: Perera Negrin, Yasser. Centro de Ingeniería Genética y Biotecnología. Laboratorio de Oncología Molecular; Cuba
Fil: Alonso, Daniel Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Perea, Silvio E.. Centro de Ingeniería Genética y Biotecnología. Laboratorio de Oncología Molecular; Cuba
Fil: Gomez, Daniel Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
Fil: Farina, Hernán Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Quilmes. Departamento de Ciencia y Tecnología. Laboratorio de Oncología Molecular; Argentina
description CIGB-300 is a cyclic synthetic peptide that induces apoptosis in malignant cells, elicits antitumor activity in cancer animal models, and shows tumor reduction signs when assayed in first-in-human phase I trial in patients with cervical tumors. CIGB-300 impairs phosphorylation by casein kinase 2 through targeting the substrate´s phosphoacceptor domain. CIGB-300 was linked to the cell penetrating peptide Tat to facilitate the delivery into cells. Previously, we showed that CIGB-300 had a differential antiproliferative behavior in different tumor cell lines. In this work, we studied differential antiproliferative behavior in terms of cellular uptake, intracellular transportation, and degradation in tumor cell lines with dissimilar sensitivity to CIGB-300. The internalization of CIGB-300 was studied in different malignant cell lines. We found that the cell membrane heparan sulfate proteoglycans act as main receptors for extracellular CIGB-300 uptake. The most sensitive tumor cell lines showed higher intracellular incorporation of CIGB-300 in comparison to less sensitive cell lines. Furthermore, CIGB-300 uptake is time- and concentration-dependent in all studied cell lines. It was shown that CIGB-300 has the ability to penetrate cells mainly by direct membrane translocation. However, a minor proportion of the peptide uses an energy-dependent endocytic pathway mechanism to gain access into cells. CIGB-300 is internalized and transported into cells preferentially by caveolae-mediated endocytosis. Lysosomes are involved in CIGB-300 degradation; highly sensitive cell lines showed degradation at earlier times compared to low sensitive cells. Altogether, our data suggests a mechanism of internalization, vesicular transportation, and degradation for CIGB-300 in tumor cells.
publishDate 2014
dc.date.none.fl_str_mv 2014-04
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/11336/33738
Gomez, Daniel Eduardo; Farina, Hernán Gabriel; Benavent Acero, Fernando Rodrigo; Alonso, Daniel Fernando; Perera Negrin, Yasser; Perea, Silvio E.; et al.; Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell Lines; American Chemical Society; Molecular Pharmaceutics; 6; 11; 4-2014; 1798-1807
1543-8384
CONICET Digital
CONICET
url http://hdl.handle.net/11336/33738
identifier_str_mv Gomez, Daniel Eduardo; Farina, Hernán Gabriel; Benavent Acero, Fernando Rodrigo; Alonso, Daniel Fernando; Perera Negrin, Yasser; Perea, Silvio E.; et al.; Mechanisms of Cellular Uptake, Intracellular Transportation, and Degradation of CIGB-300, a Tat-Conjugated Peptide, in Tumor Cell Lines; American Chemical Society; Molecular Pharmaceutics; 6; 11; 4-2014; 1798-1807
1543-8384
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1021/mp4006062
info:eu-repo/semantics/altIdentifier/url/http://pubs.acs.org/doi/10.1021/mp4006062
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 American Chemical Society
publisher.none.fl_str_mv American Chemical Society
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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score 13.001348

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