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JNK-AKT-NF-κB controls P-glycoprotein expression to attenuate the cytotoxicity of deoxynivalenol in mammalian cells.

Abstract：

:P-glycoprotein (P-gp) plays critical roles in mediating the cytotoxicity of many drugs that are P-gp substrates. Previously, we reported that P-glycoprotein (P-gp) is the foremost efflux transporter of deoxynivalenol (DON), which is one of the most abundant mycotoxins. However, whether DON changes the expression of P-gp and its mechanism are still unclear. In this study, we found DON can induce the mRNA and protein levels of P-gp in a time- and dose-dependent manner. Mechanistically, the upregulation of P-gp expression is attributable to the induction of DON-induced proapoptotic pathways as reflected by the c-Jun N-terminal kinases (JNK) phosphorylation, AKT phosphorylation and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) translocation to the nucleus. In DON-treated cells, the mitogen-activated protein kinases (MAPK) pathways were activated; however, only JNK, but not ERK or p38, activation determined P-gp induction. Activated JNK enhances the phosphorylation of AKT, thus promoting the translocation of activated NF-κB to the nucleus to activate P-gp expression. Importantly, long-term and low-dose exposure to DON induces multidrug resistance, thus attenuating the cytotoxicity of P-gp substrates, including DON, Digoxin, Sunitinib, and Etoposide. In summary, for the first time, we report that the stepwise JNK-AKT-NF-κB pathway is related to P-gp induction and DON elicited P-gp induction induces cells to resist exogenous toxic compounds, such as DON, Digoxin, Etoposide, etc. Therefore, we propose that P-gp induction under the stress of DON represents a pattern of cell self-defense against the stress of exogenous compounds and may benefit the future rational usage of medicine or toxins.

journal_name

Biochem Pharmacol

journal_title

Biochemical pharmacology

authors

Li X,Mu P,Qiao H,Wen J,Deng Y

doi

10.1016/j.bcp.2018.08.020

subject

Has Abstract

pub_date

2018-10-01 00:00:00

pages

120-134

eissn

0006-2952

issn

1873-2968

pii

S0006-2952(18)30344-7

journal_volume

156

pub_type

杂志文章

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