Synergistic inhibition of autophagy and neddylation pathways as a novel
therapeutic approach for targeting liver cancer
#MMPMID25797246
Chen P
; Hu T
; Liang Y
; Jiang Y
; Pan Y
; Li C
; Zhang P
; Wei D
; Li P
; Jeong LS
; Chu Y
; Qi H
; Yang M
; Hoffman RM
; Dong Z
; Jia L
Oncotarget
2015[Apr]; 6
(11
): 9002-17
PMID25797246
show ga
Liver cancer is the second-most frequent cause of cancer death in the world and
is highly treatment resistant. We reported previously that inhibition of
neddylation pathway with specific NAE inhibitor MLN4924, suppressed the malignant
phenotypes of liver cancer. However, during the process, MLN4924 induces
pro-survival autophagy as a mechanism of drug resistance. Here, we report that
blockage of autophagy with clinically-available autophagy inhibitors (e.g.
chloroquine) significantly enhanced the efficacy of MLN4924 on liver cancer cells
by triggering apoptosis. Mechanistically, chloroquine enhanced MLN4924-induced
up-regulation of pro-apoptotic proteins (e.g. NOXA) and down-regulation of
anti-apoptotic proteins. Importantly, the down-regulation of NOXA expression via
siRNA silencing substantially attenuated apoptosis of liver cancer cells. Further
mechanistic studies revealed that blockage of autophagy augmented MLN4924-induced
DNA damage and reactive oxygen species (ROS) generation. The elimination of DNA
damage or blockage of ROS production significantly reduced the expression of
NOXA, and thereby attenuated apoptosis and reduced growth inhibition of liver
cancer cells. Moreover, blockage of autophagy enhanced the efficacy of MLN4924 in
an orthotopic model of human liver cancer, with induction of NOXA and apoptosis
in tumor tissues. These findings provide important preclinical evidence for
clinical investigation of synergistic inhibition of neddylation and autophagy in
liver cancer.
|Antineoplastic Agents/pharmacology/therapeutic use
[MESH]
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