Cisplatin resistance in lung cancer is mediated by MACC1 expression through PI3K/AKT signaling pathway activation.
Acta Biochim Biophys Sin (Shanghai)
; 50(8): 748-756, 2018 Aug 01.
Article
em En
| MEDLINE
| ID: mdl-29961813
ABSTRACT
One of the major obstacles hindering the treatment of lung cancer (LC) is chemoresistance; however, its mechanism remains unclear. The overexpression of the metastasis-associated in colon cancer 1 (MACC1) gene has been demonstrated to reverse chemoresistance. In the current study, the expression of MACC1 in LC cells with cisplatin resistance (Cis-Re) was investigated. Cisplatin-resistant cell sublines (A549/CR and H446/CR) were induced by stepwise escalation of cisplatin exposure. MTS and flow cytometry assays were performed to measure cell proliferation and apoptosis, respectively. Western blot analysis and qRT-PCR assays were performed to determine the changes in signaling pathway-related protein and mRNA levels, respectively. A nude mouse xenograft model was used for in vivo experiments. Our results showed that MACC1 expression was increased in the cisplatin-resistant A549/CR and H446/CR cell lines, and the resistance was reversed with a decrease of MACC1 expression. MACC1 overexpression triggered an increase of Cis-Re, which was contrary to the effect of MACC1 down-regulation. In addition, the effect of MACC1 on Cis-Re was blocked by the inhibition of the PI3K/AKT pathway, and treatment with both cisplatin and a PI3K/AKT inhibitor effectively inhibited tumor growth in xenografts with MACC1 overexpression. In conclusion, our results revealed that MACC1 increased Cis-Re partially via the PI3K/AKT signaling pathway, suggesting that MACC1 could serve as a potential target to overcome Cis-Re. Furthermore, combination therapy could alleviate Cis-Re resulted from MACC1 overexpression in patients with LC.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Cisplatino
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Resistencia a Medicamentos Antineoplásicos
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Fosfatidilinositol 3-Quinases
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Proteínas Proto-Oncogênicas c-akt
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Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Revista:
Acta Biochim Biophys Sin (Shanghai)
Assunto da revista:
BIOFISICA
/
BIOQUIMICA
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
China