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Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression

Galectin-1 (GAL1), a β-galactoside-binding protein abundantly expressed in the tumor microenvironment, has emerged as a key mechanism of chemoresistance developed by different tumors. Although increased expression of GAL1 is a hallmark of hepatocellular carcinoma (HCC) progression, aggressiveness an...

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Autores principales: Carabias, Pablo, Espelt, María V., Bacigalupo, María L., Rojas, Paola, Sarrias, Luciana, Rubin, Ayelén, Saffioti, Nicolás A., Elola, María T., Rossi, Juan P., Wolfenstein-Todel, Carlota, Rabinovich, Gabriel A., Troncoso, María F.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8786848/
https://www.ncbi.nlm.nih.gov/pubmed/35075112
http://dx.doi.org/10.1038/s41419-022-04520-6
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author Carabias, Pablo
Espelt, María V.
Bacigalupo, María L.
Rojas, Paola
Sarrias, Luciana
Rubin, Ayelén
Saffioti, Nicolás A.
Elola, María T.
Rossi, Juan P.
Wolfenstein-Todel, Carlota
Rabinovich, Gabriel A.
Troncoso, María F.
author_facet Carabias, Pablo
Espelt, María V.
Bacigalupo, María L.
Rojas, Paola
Sarrias, Luciana
Rubin, Ayelén
Saffioti, Nicolás A.
Elola, María T.
Rossi, Juan P.
Wolfenstein-Todel, Carlota
Rabinovich, Gabriel A.
Troncoso, María F.
author_sort Carabias, Pablo
collection PubMed
description Galectin-1 (GAL1), a β-galactoside-binding protein abundantly expressed in the tumor microenvironment, has emerged as a key mechanism of chemoresistance developed by different tumors. Although increased expression of GAL1 is a hallmark of hepatocellular carcinoma (HCC) progression, aggressiveness and metastasis, limited information is available on the role of this endogenous lectin in HCC resistance to chemotherapy. Moreover, the precise mechanisms underlying this effect are uncertain. HCC has evolved different mechanisms of resistance to chemotherapy including those involving the P-glycoprotein (P-gp), an ATP-dependent drug efflux pump, which controls intracellular drug concentration. Here, we investigated the molecular mechanism underlying GAL1-mediated chemoresistance in HCC cells, particularly the involvement of P-gp in this effect. Our results show that GAL1 protected HepG2 cells from doxorubicin (DOX)- and sorafenib-induced cell death in vitro. Accordingly, GAL1-overexpressing HepG2 cells generated DOX-resistant tumors in vivo. High expression of GAL1 in HepG2 cells reduced intracellular accumulation of DOX likely by increasing P-gp protein expression rather than altering its membrane localization. GAL1-mediated increase of P-gp expression involved activation of the phosphatidylinositol-3 kinase (PI3K) signaling pathway. Moreover, ‘loss-of-function’ experiments revealed that P-gp mediates GAL1-driven resistance to DOX, but not to sorafenib, in HepG2 cells. Conversely, in PLC/PRF/5 cells, P-gp protein expression was undetectable and GAL1 did not control resistance to DOX or sorafenib, supporting the critical role of P-gp in mediating GAL1 effects. Collectively, our findings suggest that GAL1 confers chemoresistance in HCC through mechanisms involving modulation of P-gp, thus emphasizing the role of this lectin as a potential therapeutic target in HCC.
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spelling pubmed-87868482022-02-07 Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression Carabias, Pablo Espelt, María V. Bacigalupo, María L. Rojas, Paola Sarrias, Luciana Rubin, Ayelén Saffioti, Nicolás A. Elola, María T. Rossi, Juan P. Wolfenstein-Todel, Carlota Rabinovich, Gabriel A. Troncoso, María F. Cell Death Dis Article Galectin-1 (GAL1), a β-galactoside-binding protein abundantly expressed in the tumor microenvironment, has emerged as a key mechanism of chemoresistance developed by different tumors. Although increased expression of GAL1 is a hallmark of hepatocellular carcinoma (HCC) progression, aggressiveness and metastasis, limited information is available on the role of this endogenous lectin in HCC resistance to chemotherapy. Moreover, the precise mechanisms underlying this effect are uncertain. HCC has evolved different mechanisms of resistance to chemotherapy including those involving the P-glycoprotein (P-gp), an ATP-dependent drug efflux pump, which controls intracellular drug concentration. Here, we investigated the molecular mechanism underlying GAL1-mediated chemoresistance in HCC cells, particularly the involvement of P-gp in this effect. Our results show that GAL1 protected HepG2 cells from doxorubicin (DOX)- and sorafenib-induced cell death in vitro. Accordingly, GAL1-overexpressing HepG2 cells generated DOX-resistant tumors in vivo. High expression of GAL1 in HepG2 cells reduced intracellular accumulation of DOX likely by increasing P-gp protein expression rather than altering its membrane localization. GAL1-mediated increase of P-gp expression involved activation of the phosphatidylinositol-3 kinase (PI3K) signaling pathway. Moreover, ‘loss-of-function’ experiments revealed that P-gp mediates GAL1-driven resistance to DOX, but not to sorafenib, in HepG2 cells. Conversely, in PLC/PRF/5 cells, P-gp protein expression was undetectable and GAL1 did not control resistance to DOX or sorafenib, supporting the critical role of P-gp in mediating GAL1 effects. Collectively, our findings suggest that GAL1 confers chemoresistance in HCC through mechanisms involving modulation of P-gp, thus emphasizing the role of this lectin as a potential therapeutic target in HCC. Nature Publishing Group UK 2022-01-24 /pmc/articles/PMC8786848/ /pubmed/35075112 http://dx.doi.org/10.1038/s41419-022-04520-6 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Carabias, Pablo
Espelt, María V.
Bacigalupo, María L.
Rojas, Paola
Sarrias, Luciana
Rubin, Ayelén
Saffioti, Nicolás A.
Elola, María T.
Rossi, Juan P.
Wolfenstein-Todel, Carlota
Rabinovich, Gabriel A.
Troncoso, María F.
Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression
title Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression
title_full Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression
title_fullStr Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression
title_full_unstemmed Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression
title_short Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression
title_sort galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of p-glycoprotein expression
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8786848/
https://www.ncbi.nlm.nih.gov/pubmed/35075112
http://dx.doi.org/10.1038/s41419-022-04520-6
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