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. 2023 Dec 7;16(12):1697.
doi: 10.3390/ph16121697.

Cranberry Proanthocyanidins Mitigate Reflux-Induced Transporter Dysregulation in an Esophageal Adenocarcinoma Model

Yun Zhang  1 , Katherine M Weh  1 , Bridget A Tripp  2 , Jennifer L Clarke  3 , Connor L Howard  1 , Shruthi Sunilkumar  1 , Amy B Howell  4 , Laura A Kresty  1
Affiliations

Cranberry Proanthocyanidins Mitigate Reflux-Induced Transporter Dysregulation in an Esophageal Adenocarcinoma Model

Yun Zhang et al. Pharmaceuticals (Basel). .

Abstract

We recently reported that cranberry proanthocyanidins (C-PACs) inhibit esophageal adenocarcinoma (EAC) by 83% through reversing reflux-induced bacterial, inflammatory and immune-implicated proteins and genes as well as reducing esophageal bile acids, which drive EAC progression. This study investigated whether C-PACs' mitigation of bile reflux-induced transporter dysregulation mechanistically contributes to EAC prevention. RNA was isolated from water-, C-PAC- and reflux-exposed rat esophagi with and without C-PAC treatment. Differential gene expression was determined by means of RNA sequencing and RT-PCR, followed by protein assessments. The literature, coupled with the publicly available Gene Expression Omnibus dataset GSE26886, was used to assess transporter expression levels in normal and EAC patient biopsies for translational relevance. Significant changes in ATP-binding cassette (ABC) transporters implicated in therapeutic resistance in humans (i.e., Abcb1, Abcb4, Abcc1, Abcc3, Abcc4, Abcc6 and Abcc10) and the transport of drugs, xenobiotics, lipids, and bile were altered in the reflux model with C-PACs' mitigating changes. Additionally, C-PACs restored reflux-induced changes in solute carrier (SLC), aquaporin, proton and cation transporters (i.e., Slc2a1, Slc7a11, Slc9a1, Slco2a1 and Atp6v0c). This research supports the suggestion that transporters merit investigation not only for their roles in metabolism and therapeutic resistance, but as targets for cancer prevention and targeting preventive agents in combination with chemotherapeutics.

Keywords: ATP-binding cassette transporters; Barrett’s esophagus; aquaporins; cancer prevention; cation transporters; cranberry proanthocyanidins; gastroesophageal reflux disease; plant polyphenols; proton transporters; reflux-induced esophageal adenocarcinoma; solute carrier transporters.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Dysregulation of ABC and SLC transporters in human EAC. (a) Differentially expressed transporters identified in the human EAC GEO26886 dataset comparing normal non-cancer tissues to EAC patient tissues and with the same directionality of change observed in the reflux-induced EAC rat model. (b) Differentially expressed transporters in the human EAC GEO26886 dataset with the opposite directionality compared to the rat reflux-induced EAC model. Dashed lines indicate the mean normalized transcript-per-million (TPM) value in each group. (c) Immunoblot of ASBT (encoded by SLC10A2) in patient-matched normal, BE, and EAC samples. ND, not detected.
Figure 2
Figure 2
STRING network interaction of the major transporters and proteins altered in the rat reflux-induced EAC model and mitigated by C-PACs. Colored lines as shown in the legend define the basis and the type of interaction between the molecules in the model. All transporters included have been identified as being altered in human EAC compared to normal esophageal tissues from non-cancer patients.
Figure 3
Figure 3
C-PACs mitigate the dysregulation of transporters and key regulatory genes in reflux-induced EAC. (a) Dysregulation of ABCB1 in reflux-induced EAC and mitigation by C-PACs. (b) Reflux-induced EAC led to increased expression of stress response-related proteins and upregulation of CD44 with linkages to inflammation, bacterial sensing and the immune state. C-PACs mitigate reflux-induced protein induction. ND, not detected.
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