Cargando…

Metformin suppresses proliferation and invasion of drug‐resistant breast cancer cells by activation of the Hippo pathway

Drug resistance limits the clinical efficacy of breast cancer therapies, and overexpression or activation of Yes‐associated protein (YAP) is common in drug‐resistant cancer cells. Thus, inhibition of YAP may reduce resistance to anti‐cancer drugs. Metformin (MET), a first‐line diabetes medication th...

Descripción completa

Detalles Bibliográficos
Autores principales: Liu, Jie, Li, Juan, Chen, He, Wang, Ruiqi, Li, Pingping, Miao, Yi, Liu, Peijun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214175/
https://www.ncbi.nlm.nih.gov/pubmed/32281270
http://dx.doi.org/10.1111/jcmm.15241
_version_ 1783531918826930176
author Liu, Jie
Li, Juan
Chen, He
Wang, Ruiqi
Li, Pingping
Miao, Yi
Liu, Peijun
author_facet Liu, Jie
Li, Juan
Chen, He
Wang, Ruiqi
Li, Pingping
Miao, Yi
Liu, Peijun
author_sort Liu, Jie
collection PubMed
description Drug resistance limits the clinical efficacy of breast cancer therapies, and overexpression or activation of Yes‐associated protein (YAP) is common in drug‐resistant cancer cells. Thus, inhibition of YAP may reduce resistance to anti‐cancer drugs. Metformin (MET), a first‐line diabetes medication that also has anti‐tumour activities, induces AMP‐activated protein kinase (AMPK), directly phosphorylates YAP and inhibits YAP transcriptional activity. In this study, we determined the effect of MET on the proliferation and invasion of drug‐resistant breast cancer cells and then investigated the underlying molecular mechanism. Our in vivo and in vitro experiments indicated that MET suppressed breast cancer by an AMPK‐independent pathway to decrease YAP nuclear localization. In drug‐sensitive cells, MET activated the Hippo pathway by increasing KIBRA and FRMD6 expression, but this did not occur in drug‐resistant cells. Scribble (SCRIB), a cell polarity protein, was notably down‐regulated in tamoxifen‐ and paclitaxel‐resistant breast cancer cells relative to sensitive cells. We also found that MET suppressed the proliferation and invasion of drug‐resistant breast cancer cells by increasing the expression and cell membrane localization of SCRIB, which enhanced the interaction of SCRIB with MST1 and LATS1, and inhibited YAP nuclear localization and transcriptional activity.
format Online
Article
Text
id pubmed-7214175
institution National Center for Biotechnology Information
language English
publishDate 2020
publisher John Wiley and Sons Inc.
record_format MEDLINE/PubMed
spelling pubmed-72141752020-05-13 Metformin suppresses proliferation and invasion of drug‐resistant breast cancer cells by activation of the Hippo pathway Liu, Jie Li, Juan Chen, He Wang, Ruiqi Li, Pingping Miao, Yi Liu, Peijun J Cell Mol Med Original Articles Drug resistance limits the clinical efficacy of breast cancer therapies, and overexpression or activation of Yes‐associated protein (YAP) is common in drug‐resistant cancer cells. Thus, inhibition of YAP may reduce resistance to anti‐cancer drugs. Metformin (MET), a first‐line diabetes medication that also has anti‐tumour activities, induces AMP‐activated protein kinase (AMPK), directly phosphorylates YAP and inhibits YAP transcriptional activity. In this study, we determined the effect of MET on the proliferation and invasion of drug‐resistant breast cancer cells and then investigated the underlying molecular mechanism. Our in vivo and in vitro experiments indicated that MET suppressed breast cancer by an AMPK‐independent pathway to decrease YAP nuclear localization. In drug‐sensitive cells, MET activated the Hippo pathway by increasing KIBRA and FRMD6 expression, but this did not occur in drug‐resistant cells. Scribble (SCRIB), a cell polarity protein, was notably down‐regulated in tamoxifen‐ and paclitaxel‐resistant breast cancer cells relative to sensitive cells. We also found that MET suppressed the proliferation and invasion of drug‐resistant breast cancer cells by increasing the expression and cell membrane localization of SCRIB, which enhanced the interaction of SCRIB with MST1 and LATS1, and inhibited YAP nuclear localization and transcriptional activity. John Wiley and Sons Inc. 2020-04-12 2020-05 /pmc/articles/PMC7214175/ /pubmed/32281270 http://dx.doi.org/10.1111/jcmm.15241 Text en © 2020 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Liu, Jie
Li, Juan
Chen, He
Wang, Ruiqi
Li, Pingping
Miao, Yi
Liu, Peijun
Metformin suppresses proliferation and invasion of drug‐resistant breast cancer cells by activation of the Hippo pathway
title Metformin suppresses proliferation and invasion of drug‐resistant breast cancer cells by activation of the Hippo pathway
title_full Metformin suppresses proliferation and invasion of drug‐resistant breast cancer cells by activation of the Hippo pathway
title_fullStr Metformin suppresses proliferation and invasion of drug‐resistant breast cancer cells by activation of the Hippo pathway
title_full_unstemmed Metformin suppresses proliferation and invasion of drug‐resistant breast cancer cells by activation of the Hippo pathway
title_short Metformin suppresses proliferation and invasion of drug‐resistant breast cancer cells by activation of the Hippo pathway
title_sort metformin suppresses proliferation and invasion of drug‐resistant breast cancer cells by activation of the hippo pathway
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214175/
https://www.ncbi.nlm.nih.gov/pubmed/32281270
http://dx.doi.org/10.1111/jcmm.15241
work_keys_str_mv AT liujie metforminsuppressesproliferationandinvasionofdrugresistantbreastcancercellsbyactivationofthehippopathway
AT lijuan metforminsuppressesproliferationandinvasionofdrugresistantbreastcancercellsbyactivationofthehippopathway
AT chenhe metforminsuppressesproliferationandinvasionofdrugresistantbreastcancercellsbyactivationofthehippopathway
AT wangruiqi metforminsuppressesproliferationandinvasionofdrugresistantbreastcancercellsbyactivationofthehippopathway
AT lipingping metforminsuppressesproliferationandinvasionofdrugresistantbreastcancercellsbyactivationofthehippopathway
AT miaoyi metforminsuppressesproliferationandinvasionofdrugresistantbreastcancercellsbyactivationofthehippopathway
AT liupeijun metforminsuppressesproliferationandinvasionofdrugresistantbreastcancercellsbyactivationofthehippopathway