HBV infection potentiates resistance to S-phase arrest-inducing chemotherapeutics by inhibiting CHK2 pathway in diffuse large B-cell lymphoma.
Cell Death Dis
; 9(2): 61, 2018 01 19.
Article
em En
| MEDLINE
| ID: mdl-29352124
ABSTRACT
A considerable number of diffuse large B-cell lymphoma (DLBCL) patients are infected with hepatitis B virus (HBV), which is correlated with their poor outcomes. However, the role of HBV infection in DLBCL treatment failure remains poorly understood. Here, our data demonstrated that HBV infection was closely associated with poorer clinical prognosis independent of its hepatic dysfunction in germinal center B-cell type (GCB type) DLBCL patients. Interestingly, we found that DLBCL cells expressing hepatitis B virus X protein (HBX) did not exhibit enhanced cell growth but did show reduced sensitivity to methotrexate (MTX) and cytarabine (Ara-C), which induced S-phase arrest. Mechanism studies showed that HBX specifically inhibited the phosphorylation of checkpoint kinase 2 (CHK2, a key DNA damage response protein). CHK2 depletion similarly conferred resistance to the S-phase arrest-inducing chemotherapeutics, consistent with HBX overexpression in DLBCL cells. Moreover, overexpression of wild-type CHK2 rather than its unphosphorylated mutant (T68A) significantly restored the reduced chemosensitivity in HBX-expressing cells, suggesting that HBV infection conferred resistance to chemotherapeutics that induced S-phase arrest by specifically inhibiting the activation of CHK2 response signaling in DLBCL.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ciclo Celular
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Vírus da Hepatite B
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Linfoma Difuso de Grandes Células B
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Quinase do Ponto de Checagem 2
Limite:
Female
/
Humans
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Male
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Middle aged
Idioma:
En
Revista:
Cell Death Dis
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
China