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. 2014 Sep 1;33(1):73.
doi: 10.1186/s13046-014-0073-x.

Proton pump inhibitors (PPIs) impact on tumour cell survival, metastatic potential and chemotherapy resistance, and affect expression of resistance-relevant miRNAs in esophageal cancer

Kirsten Lindner  1 , Christiane Borchardt  2 , Maren Schöpp  3 , Anja Bürgers  4 , Christian Stock  5 , Damian J Hussey  6 , Jörg Haier  7 , Richard Hummel  8
Affiliations

Proton pump inhibitors (PPIs) impact on tumour cell survival, metastatic potential and chemotherapy resistance, and affect expression of resistance-relevant miRNAs in esophageal cancer

Kirsten Lindner et al. J Exp Clin Cancer Res. .

Abstract

Background: Neoadjuvant treatment plays a crucial role in the therapy of advanced esophageal cancer. However, response to radiochemotherapy varies widely. Proton pump inhibitors (PPIs) have been demonstrated to impact on chemotherapy in a variety of other cancers. We analyzed the impact of PPI treatment on esophageal cancer cell lines, and investigated mechanisms that mediate the effect of PPI treatment in this tumour.

Methods: We investigated the effect of esomeprazole treatment on cancer cell survival, adhesion, migration and chemotherapy in human adeno-(OE19) and squamous-cell-carcinoma (KYSE410) cell lines. Furthermore, we investigated the effect of PPI treatment on intra-/extracellular pH and on expression of resistance-relevant miRNAs.

Results: Esomeprazole significantly inhibited tumour cell survival (in a dose-dependent manner), adhesion and migration in both tumour subtypes. Furthermore, esomeprazole augmented the cytotoxic effect of cisplatin and 5-FU in both tumour subtypes. Surprisingly, PPI treatment led to a significant increase of intracellular pH and a decrease of the extracellular pH. Finally, we found esomeprazole affected expression of resistance-relevant miRNAs. Specifically, miR-141 and miR-200b were upregulated, whereas miR-376a was downregulated after PPI treatment in both tumour types.

Conclusion: Our study demonstrates for the first time that PPIs impact on tumour cell survival, metastatic potential and sensitivity towards chemotherapy in esophageal cancer cell lines. Furthermore, we observed that in this tumour entity, PPIs do not lead to intracellular acidification, but affect the expression of resistance-relevant miRNAs.

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Figures

Figure 1
Figure 1
Dose¿response curve of PPI treatment in esophageal cancer cell lines. The figure presents an overview of the impact of PPI treatment with esomeprazole on tumour cell survival in SCC (A) and EAC (B) cells. PPI: proton pump inhibitor esomeprazole.
Figure 2
Figure 2
Effect of PPI treatment on metastatic potential of esophageal cancer cell lines. The figure presents an overview about the effect of PPI treatment on cell adhesion (1) and migration (2) in SCC (A) and EAC (B) cell lines. Negative controls (i.e. adhesion and migration assays with uncoated wells) were performed though for visual clarity they are not included in the figures. PPI treatment: treatment with proton pump inhibitor esomeprazole. Control: untreated control cells. *: statistically significant different compared to control (p???0.025).
Figure 3
Figure 3
Effect of PPI treatment on otherwise untreated cells and on CTX treated cells. Presents an overview of the impact of esomeprazole treatment on otherwise untreated cells or on cells that were treated simultaneously with chemotherapeutics (3A: SCC; 3B: EAC). Tumour cells were treated with either esomeprazole alone at different concentrations (50 ?M: ¿sub-lethal¿, 86-100% cell survival; 250 ?M: ¿lethal¿, 20-30% cell survival; 350 ?M: ¿highly lethal¿, <10% cell survival), or with cisplatin or 5-FU at the respective LD50 concentrations, or with esomeprazole and chemotherapeutics together. The upper graphs present an overview of the relative cell survival of the respective groups (PPI treated cells versus chemotherapy (CTX) treated cells versus PPI?+?CTX treated cells). The lower graphs present an overview about the additional cytotoxic effect of PPI treatment on otherwise untreated cells (PPI w/o CTX) or on CTX treated cells (PPI w CTX). PPI: proton pump inhibitor esomeprazole. CTX: chemotherapy. *: statistically significant different compared to control.
Figure 4
Figure 4
Effect of PPI treatment on intracellular pH. The figure presents the results of intracellular pH measurement after 24/48/72 hours of esomeprazole treatment (LD50) in SCC (A) and EAC (B) cells. PPI treatment: treatment with esomeprazole. *: statistically significant different compared to control (p???0.017).
Figure 5
Figure 5
Effect of PPI treatment on extracellular proton concentration. The figure presents the concentration of protons in the extracellular space (culture medium) after 72 hour PPI treatment (LD50) in SCC (A) and EAC (B) cells. *: statistically significant different compared to control (p???0.001).
Figure 6
Figure 6
Effect of PPI treatment on expression of resistance-relevant miRNAs. The figure presents an overview about the significant deregulation of selected miRNAs in SCC and EAC cells in after treatment with esomeprazole (LD50) for 72 hours, compared to controls. ?: significant upregulation. ?: significant downregulation.
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