| Autor: |
Lam Eric, Stavropoulou Alexandra V, Alao John P, Coombes R Charles |
| Jazyk: |
angličtina |
| Rok vydání: |
2006 |
| Předmět: |
|
| Zdroj: |
Molecular Cancer, Vol 5, Iss 1, p 40 (2006) |
| Druh dokumentu: |
article |
| ISSN: |
1476-4598 |
| DOI: |
10.1186/1476-4598-5-40 |
| Popis: |
Abstract Histone deacetylase inhibitors (HDACIs) have been shown to induce apoptotic and autophagic cell death in vitro and in vivo. 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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