Role of glycogen synthase kinase 3 beta (GSK3β) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells
<p>Abstract</p> <p>Histone deacetylase inhibitors (HDACIs) have been shown to induce apoptotic and autophagic cell death <it>in vitro </it>and <it>in vivo</it>. The molecular mechanisms that underlie these cytotoxic effects are not yet clearly understood. Re...
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| Format: | Article |
| Language: | English |
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BMC
2006-10-01
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| Series: | Molecular Cancer |
| Online Access: | http://www.molecular-cancer.com/content/5/1/40 |
| _version_ | 1828469347666886656 |
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| author | Lam Eric Stavropoulou Alexandra V Alao John P Coombes R Charles |
| author_facet | Lam Eric Stavropoulou Alexandra V Alao John P Coombes R Charles |
| author_sort | Lam Eric |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Histone deacetylase inhibitors (HDACIs) have been shown to induce apoptotic and autophagic cell death <it>in vitro </it>and <it>in vivo</it>. The molecular mechanisms that underlie these cytotoxic effects are not yet clearly understood. Recently, HDACIs were shown to induce Akt dephosphorylation by disrupting HDAC-protein phosphatase 1 (PP1) complexes. This disruption results in the increased association of PP1 with Akt, resulting in the dephosphorylation and consequent inactivation of the kinase. Akt enhances cellular survival through the phosphorylation-dependent inhibition of several pro-apoptotic proteins. Akt is an important negative regulator of GSK3β, a kinase that has been shown to regulate apoptosis in response to various stimuli. In the present study, we investigated the role of GSK3β in mediating the cytotoxic effects in MCF-7 breast cancer cells treated with trichostatin A (TSA), a prototype HDACI. We show that TSA induces Akt dephosphorylation in a PP1-dependent manner, resulting in activation of GSK3β in MCF-7 cells. Similarly, knockdown of HDAC1 and-2 by small interfering RNA (siRNA) resulted in the dephosphorylation of Akt and GSK3β. Selective inhibition of GSK3β attenuated TSA induced cytotoxicity and resulted in enhanced proliferation following drug removal. Our findings identify GSK3β as an important mediator of TSA-induced cytotoxicity in MCF-7 breast cancer cells.</p> |
| first_indexed | 2024-12-11T04:38:05Z |
| format | Article |
| id | doaj.art-b8a80279313e484b81f795f1ef181441 |
| institution | Directory Open Access Journal |
| issn | 1476-4598 |
| language | English |
| last_indexed | 2024-12-11T04:38:05Z |
| publishDate | 2006-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Cancer |
| spelling | doaj.art-b8a80279313e484b81f795f1ef1814412022-12-22T01:20:42ZengBMCMolecular Cancer1476-45982006-10-01514010.1186/1476-4598-5-40Role of glycogen synthase kinase 3 beta (GSK3β) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cellsLam EricStavropoulou Alexandra VAlao John PCoombes R Charles<p>Abstract</p> <p>Histone deacetylase inhibitors (HDACIs) have been shown to induce apoptotic and autophagic cell death <it>in vitro </it>and <it>in vivo</it>. The molecular mechanisms that underlie these cytotoxic effects are not yet clearly understood. Recently, HDACIs were shown to induce Akt dephosphorylation by disrupting HDAC-protein phosphatase 1 (PP1) complexes. This disruption results in the increased association of PP1 with Akt, resulting in the dephosphorylation and consequent inactivation of the kinase. Akt enhances cellular survival through the phosphorylation-dependent inhibition of several pro-apoptotic proteins. Akt is an important negative regulator of GSK3β, a kinase that has been shown to regulate apoptosis in response to various stimuli. In the present study, we investigated the role of GSK3β in mediating the cytotoxic effects in MCF-7 breast cancer cells treated with trichostatin A (TSA), a prototype HDACI. We show that TSA induces Akt dephosphorylation in a PP1-dependent manner, resulting in activation of GSK3β in MCF-7 cells. Similarly, knockdown of HDAC1 and-2 by small interfering RNA (siRNA) resulted in the dephosphorylation of Akt and GSK3β. Selective inhibition of GSK3β attenuated TSA induced cytotoxicity and resulted in enhanced proliferation following drug removal. Our findings identify GSK3β as an important mediator of TSA-induced cytotoxicity in MCF-7 breast cancer cells.</p>http://www.molecular-cancer.com/content/5/1/40 |
| spellingShingle | Lam Eric Stavropoulou Alexandra V Alao John P Coombes R Charles Role of glycogen synthase kinase 3 beta (GSK3β) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells Molecular Cancer |
| title | Role of glycogen synthase kinase 3 beta (GSK3β) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells |
| title_full | Role of glycogen synthase kinase 3 beta (GSK3β) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells |
| title_fullStr | Role of glycogen synthase kinase 3 beta (GSK3β) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells |
| title_full_unstemmed | Role of glycogen synthase kinase 3 beta (GSK3β) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells |
| title_short | Role of glycogen synthase kinase 3 beta (GSK3β) in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin A (TSA) in MCF-7 breast cancer cells |
| title_sort | role of glycogen synthase kinase 3 beta gsk3β in mediating the cytotoxic effects of the histone deacetylase inhibitor trichostatin a tsa in mcf 7 breast cancer cells |
| url | http://www.molecular-cancer.com/content/5/1/40 |
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