TG-interacting factor transcriptionally induced by AKT/FOXO3A is a negative regulator that antagonizes arsenic trioxide-induced cancer cell apoptosis.
Toxicol Appl Pharmacol
; 285(1): 41-50, 2015 May 15.
Article
em En
| MEDLINE
| ID: mdl-25791921
ABSTRACT
Arsenic trioxide (ATO) is a multi-target drug approved by the Food and Drug Administration as the first-line chemotherapeutic agent for the treatment of acute promyelocytic leukemia. In addition, several clinical trials are being conducted with arsenic-based drugs for the treatment of other hematological malignancies and solid tumors. However, ATO's modest clinical efficacy on some cancers, and potential toxic effects on humans have been reported. Determining how best to reduce these adverse effects while increasing its therapeutic efficacy is obviously a critical issue. Previously, we demonstrated that the JNK-induced complex formation of phosphorylated c-Jun and TG-interacting factor (TGIF) antagonizes ERK-induced cyclin-dependent kinase inhibitor CDKN1A (p21(WAF1/CIP1)) expression and resultant apoptosis in response to ATO in A431 cells. Surprisingly, at low-concentrations (0.1-0.2 µM), ATO increased cellular proliferation, migration and invasion, involving TGIF expression, however, at high-concentrations (5-20 µM), ATO induced cell apoptosis. Using a promoter analysis, TGIF was transcriptionally regulated by ATO at the FOXO3A binding site (-1486 to -1479bp) via the c-Src/EGFR/AKT pathway. Stable overexpression of TGIF promoted advancing the cell cycle into the S phase, and attenuated 20 µM ATO-induced apoptosis. Furthermore, blockage of the AKT pathway enhanced ATO-induced CDKN1A expression and resultant apoptosis in cancer cells, but overexpression of AKT1 inhibited CDKN1A expression. Therefore, we suggest that TGIF is transcriptionally regulated by the c-Src/EGFR/AKT pathway, which plays a role as a negative regulator in antagonizing ATO-induced CDKN1A expression and resultant apoptosis. Suppression of these antagonistic effects might be a promising therapeutic strategy toward improving clinical efficacy of ATO.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Óxidos
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Arsenicais
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Proteínas Repressoras
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Transcrição Gênica
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Apoptose
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Proteínas de Homeodomínio
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Proteínas Proto-Oncogênicas c-akt
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Fatores de Transcrição Forkhead
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Neoplasias
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Antineoplásicos
Limite:
Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article