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The proton pump inhibitor pantoprazole disrupts protein degradation systems and
sensitizes cancer cells to death under various stresses
#MMPMID29789637
Cao Y
; Chen M
; Tang D
; Yan H
; Ding X
; Zhou F
; Zhang M
; Xu G
; Zhang W
; Zhang S
; Zhuge Y
; Wang L
; Zou X
Cell Death Dis
2018[May]; 9
(6
): 604
PMID29789637
show ga
Proton pump inhibitors (PPIs) play a role in antitumor activity, with studies
showing specialized impacts of PPIs on cancer cell apoptosis, metastasis, and
autophagy. In this study, we demonstrated that pantoprazole (PPI) increased
autophagosomes formation and affected autophagic flux depending on the pH
conditions. PPI specifically elevated SQSTM1 protein levels by increasing SQSTM1
transcription via NFE2L2 activation independent of the specific effect of PPI on
autophagic flux. Via decreasing proteasome subunits expression, PPI significantly
impaired the function of the proteasome, accompanied by the accumulation of
undegraded poly-ubiquitinated proteins. Notably, PPI-induced autophagy functioned
as a downstream response of proteasome inhibition by PPI, while suppressing
protein synthesis abrogated autophagy. Blocking autophagic flux in neutral pH
condition or further impairing proteasome function with proteasome inhibitors,
significantly aggravated PPI cytotoxicity by worsening protein degradation
ability. Interestingly, under conditions of mitochondrial stress, PPI showed
significant synergism when combined with Bcl-2 inhibitors. Taken together, these
findings provide a new understanding of the impact of PPIs on cancer cells'
biological processes and highlight the potential to develop more efficient and
effective combination therapies.
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