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Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation

Metformin is an anti-diabetic drug and has anticancer effects on various cancers. Several studies have suggested that metformin reduces cell proliferation and stimulates cell-cycle arrest and apoptosis. However, the definitive molecular mechanism of metformin in the pathophysiological signaling in e...

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Autores principales: Rho, Seung Bae, Byun, Hyun Jung, Kim, Boh-Ram, Lee, Chang Hoon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Korean Society of Applied Pharmacology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551729/
https://www.ncbi.nlm.nih.gov/pubmed/34607979
http://dx.doi.org/10.4062/biomolther.2021.131
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author Rho, Seung Bae
Byun, Hyun Jung
Kim, Boh-Ram
Lee, Chang Hoon
author_facet Rho, Seung Bae
Byun, Hyun Jung
Kim, Boh-Ram
Lee, Chang Hoon
author_sort Rho, Seung Bae
collection PubMed
description Metformin is an anti-diabetic drug and has anticancer effects on various cancers. Several studies have suggested that metformin reduces cell proliferation and stimulates cell-cycle arrest and apoptosis. However, the definitive molecular mechanism of metformin in the pathophysiological signaling in endometrial tumorigenesis and metastasis is not clearly understood. In this study, we examined the effects of metformin on the cell viability and apoptosis of human cervical HeLa and endometrial HEC-1-A and KLE cancer cells. Metformin suppressed cell growth in a dose-dependent manner and dramatically evoked apoptosis in HeLa cervical cancer cells, while apoptotic cell death and growth inhibition were not observed in endometrial (HEC-1-A, KLE) cell lines. Accordingly, the p27 and p21 promoter activities were enhanced while Bcl-2 and IL-6 activities were significantly reduced by metformin treatment. Metformin diminished the phosphorylation of mTOR, p70S6K and 4E-BP1 by accelerating adenosine monophosphate-activated kinase (AMPK) in HeLa cancer cells, but it did not affect other cell lines. To determine why the anti-proliferative effects are observed only in HeLa cells, we examined the expression level of liver kinase B1 (LKB1) since metformin and LKB1 share the same signalling system, and we found that the LKB1 gene is not expressed only in HeLa cancer cells. Consistently, the overexpression of LKB1 in HeLa cancer cells prevented metformin-triggered apoptosis while LKB1 knockdown significantly increased apoptosis in HEC-1-A and KLE cancer cells. Taken together, these findings indicate an underlying biological/physiological molecular function specifically for metformin-triggered apoptosis dependent on the presence of the LKB1 gene in tumorigenesis.
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spelling pubmed-85517292021-10-31 Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation Rho, Seung Bae Byun, Hyun Jung Kim, Boh-Ram Lee, Chang Hoon Biomol Ther (Seoul) Original Article Metformin is an anti-diabetic drug and has anticancer effects on various cancers. Several studies have suggested that metformin reduces cell proliferation and stimulates cell-cycle arrest and apoptosis. However, the definitive molecular mechanism of metformin in the pathophysiological signaling in endometrial tumorigenesis and metastasis is not clearly understood. In this study, we examined the effects of metformin on the cell viability and apoptosis of human cervical HeLa and endometrial HEC-1-A and KLE cancer cells. Metformin suppressed cell growth in a dose-dependent manner and dramatically evoked apoptosis in HeLa cervical cancer cells, while apoptotic cell death and growth inhibition were not observed in endometrial (HEC-1-A, KLE) cell lines. Accordingly, the p27 and p21 promoter activities were enhanced while Bcl-2 and IL-6 activities were significantly reduced by metformin treatment. Metformin diminished the phosphorylation of mTOR, p70S6K and 4E-BP1 by accelerating adenosine monophosphate-activated kinase (AMPK) in HeLa cancer cells, but it did not affect other cell lines. To determine why the anti-proliferative effects are observed only in HeLa cells, we examined the expression level of liver kinase B1 (LKB1) since metformin and LKB1 share the same signalling system, and we found that the LKB1 gene is not expressed only in HeLa cancer cells. Consistently, the overexpression of LKB1 in HeLa cancer cells prevented metformin-triggered apoptosis while LKB1 knockdown significantly increased apoptosis in HEC-1-A and KLE cancer cells. Taken together, these findings indicate an underlying biological/physiological molecular function specifically for metformin-triggered apoptosis dependent on the presence of the LKB1 gene in tumorigenesis. The Korean Society of Applied Pharmacology 2021-11-01 2021-10-05 /pmc/articles/PMC8551729/ /pubmed/34607979 http://dx.doi.org/10.4062/biomolther.2021.131 Text en Copyright © 2021, The Korean Society of Applied Pharmacology https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0 (https://creativecommons.org/licenses/by-nc/4.0/) ) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Article
Rho, Seung Bae
Byun, Hyun Jung
Kim, Boh-Ram
Lee, Chang Hoon
Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation
title Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation
title_full Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation
title_fullStr Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation
title_full_unstemmed Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation
title_short Knockdown of LKB1 Sensitizes Endometrial Cancer Cells via AMPK Activation
title_sort knockdown of lkb1 sensitizes endometrial cancer cells via ampk activation
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8551729/
https://www.ncbi.nlm.nih.gov/pubmed/34607979
http://dx.doi.org/10.4062/biomolther.2021.131
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