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The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses.

ABSTRACT: 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.

SUBMITTER: Cao Y

PROVIDER: S-EPMC5964200 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses.

Cao Yu Y Chen Min M Tang Dehua D Yan Hongli H Ding Xiwei X Zhou Fan F Zhang Mingming M Xu Guifang G Zhang Weijie W Zhang Shu S Zhuge Yuzheng Y Wang Lei L Zou Xiaoping X

Cell death & disease 20180522 6

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 ...[more]

PMID: 29789637

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Project description:Symbiotic bacteria, commonly called rhizobia, lead a saprophytic lifestyle in the soil and form nitrogen-fixing nodules on legume roots. During their lifecycle, rhizobia have to adapt to different conditions prevailing in the soils and within host plants. To survive under these conditions, rhizobia fine-tune the regulatory machinery to respond rapidly and adequately to environmental changes. Symbiotic bacteria play an essential role in the soil environment from both ecological and economical point of view, since these bacteria provide Fabaceae plants (legumes) with large amounts of accessible nitrogen as a result of symbiotic interactions (i.e., rhizobia present within the nodule reduce atmospheric dinitrogen (N2) to ammonia, which can be utilized by plants). Because of its restricted availability in the soil, nitrogen is one of the most limiting factors for plant growth. In spite of its high content in the atmosphere, plants are not able to assimilate it directly in the N2 form. During symbiosis, rhizobia infect host root and trigger the development of specific plant organ, the nodule. The aim of root nodule formation is to ensure a microaerobic environment, which is essential for proper activity of nitrogenase, i.e., a key enzyme facilitating N2 fixation. To adapt to various lifestyles and environmental stresses, rhizobia have developed several regulatory mechanisms, e.g., reversible phosphorylation. This key mechanism regulates many processes in both prokaryotic and eukaryotic cells. In microorganisms, signal transduction includes two-component systems (TCSs), which involve membrane sensor histidine kinases (HKs) and cognate DNA-binding response regulators (RRs). Furthermore, regulatory mechanisms based on phosphoenolopyruvate-dependent phosphotranspherase systems (PTSs), as well as alternative regulatory pathways controlled by Hanks-type serine/threonine kinases (STKs) and serine/threonine phosphatases (STPs) play an important role in regulation of many cellular processes in both free-living bacteria and during symbiosis with the host plant (e.g., growth and cell division, envelope biogenesis, biofilm formation, response to stress conditions, and regulation of metabolism). In this review, we summarize the current knowledge of phosphorylation systems in symbiotic nitrogen-fixing bacteria, and their role in the physiology of rhizobial cells and adaptation to various environmental conditions.

Project description:BackgroundEsophageal eosinophilia can be proton pump inhibitor (PPI) resistant or responsive, representing 2 entities known as eosinophilic esophagitis (EoE) and PPI-responsive esophageal eosinophilia (PPI-REE), respectively. Although they present with similar clinical features, EoE is accepted to be an antigen-driven, TH2-associated allergic disorder, whereas the cause of PPI-REE remains a mystery.ObjectiveIn this study, our aim was to investigate the pathogenesis of PPI-REE by using a recently described EoE diagnostic panel (EDP) composed of a set of 94 esophageal transcripts and to determine whether PPI therapy reverses any esophageal transcriptional abnormalities.MethodsWe evaluated the EDP signature in biopsy samples obtained from adult and pediatric patients with PPI-REE from 4 institutions and compared the pre- and post-PPI therapy expression profiles of these subjects with those of patients with active EoE.ResultsThe EDP differentiated patients with EoE from control subjects with 100% accuracy among the 4 clinical sites. Bioinformatics analysis revealed largely overlapping transcriptomes between patients with PPI-REE and those with EoE, including the genes for eosinophil chemotaxis (eotaxin 3, CCL26), barrier molecules (desmoglein 1, DSG1), tissue remodeling (periostin, POSTN), and mast cells (carboxypeptidase A, CPA3). PPI monotherapy alone almost completely reversed the allergic inflammatory transcriptome of patients with PPI-REE. Furthermore, we identified a set of candidate genes to differentiate patients with EoE from those with PPI-REE before treatment.ConclusionThese findings provide definitive evidence that PPI-REE is a disease entity with significant molecular overlap with EoE, suggesting that many patients with PPI-REE represent a continuum of the same pathogenic allergic mechanisms that underlie EoE and thus might constitute a subphenotype of patients with EoE. The ability of PPI therapy to nearly entirely reverse gene expression associated with PPI-REE, particularly that associated with classic features of allergic inflammation, provides new insight into potential disease etiology and management strategies for patients with significant esophageal eosinophilia.

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The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses.

Publications

The proton pump inhibitor pantoprazole disrupts protein degradation systems and sensitizes cancer cells to death under various stresses.

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