Constitutively Higher Level of GSTT2 in Esophageal Tissues From African Americans Protects Cells Against DNA Damage

Ferrer-Torres, Daysha; Nancarrow, Derek J.; Steinberg, Hannah D.; Wang, Zhuwen; Kuick, Rork; Weh, Katherine M.; Mills, Ryan E.; Ray, Dipankar; Ray, Paramita; Lin, Jules; Chang, Andrew C.; Reddy, Rishindra M.; Canto, Marcia I.; Shaheen, Nicholas J.; Kresty, Laura A.; Chak, Amitabh; Wang, Thomas D.; Rubenstein, Joel H.; Beer, David G.

doi:10.1053/j.gastro.2018.12.004

Cited by 21 publications

(38 citation statements)

References 39 publications

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“…These different variants are associated with higher expression of the enzyme in African American. The findings may explain the inherent different susceptibility risk to Barrett's esophagus in the population [ 51 ]. Furthermore, there are accumulating lines of evidence showing that the cellular anti-oxidants capacity is compromised during BE-EAC tumorigenesis ( Fig.…”

Section: Dysfunction Of Anti-oxidant Enzymes Contributes To Oxidativementioning

confidence: 99%

The antioxidant response in Barrett's tumorigenesis: A double-edged sword

et al. 2021

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Esophageal adenocarcinoma (EAC) is the dominant form of esophageal malignancies in the United States and other industrialized countries. The incidence of EAC has been rising rapidly during the past four decades. Barrett's esophagus (BE) is the main precancerous condition for EAC, where a metaplastic columnar epithelium replaces normal squamous mucosa of the lower esophagus. The primary risk factor for BE and EAC are chronic gastroesophageal reflux disease (GERD), obesity and smoking. During the BE-dysplasia-EAC sequence, esophageal cells are under a tremendous burden of accumulating reactive oxygen species (ROS) and oxidative stress. While normal cells have intact antioxidant machinery to maintain a balanced anti-tumorigenic physiological response, the antioxidant capacity is compromised in neoplastic cells with a pro-tumorigenic development antioxidant response. The accumulation of ROS, during the neoplastic progression of the GERD-BE-EAC sequence, induces DNA damage, lipid peroxidation and protein oxidation. Neoplastic cells adapt to oxidative stress by developing a pro-tumorigenic antioxidant response that keeps oxidative damage below lethal levels while promoting tumorigenesis, progression, and resistance to therapy. In this review, we will summarize the recent findings on oxidative stress in tumorigenesis in the context of the GERD-BE-EAC process. We will discuss how EAC cells adapt to increased ROS. We will review APE1 and NRF2 signaling mechanisms in the context of EAC. Finally, we will discuss the potential clinical significance of applying antioxidants or NRF2 activators as chemoprevention and NRF2 inhibitors in treating EAC patients.

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Section: Dysfunction Of Anti-oxidant Enzymes Contributes To Oxidativementioning

confidence: 99%

The antioxidant response in Barrett's tumorigenesis: A double-edged sword

et al. 2021

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“…Clinical studies have shown that AA populations have significantly less esophageal disease including Barrett’s Esophagus and a lower incidence of EAC when compared to EA patients (El-Serag, HB and Sonnenberg, 1997; El-Serag et al ., 2014). Messenger RNA analyses of cohorts of AA and EA patient-derived esophageal biopsies in healthy and diseased states revealed differences in the mRNA expression of the enzyme GSTT2 in these patients (Ferrer-Torres et al ., 2019), with the AA biopsies possessing significantly higher GSTT2 mRNA levels. However, the cellular tools to study the mechanisms underlying these racial differences and to interrogate GSTT2 in both AA and EA tissue models, were lacking.…”

Section: Discussionmentioning

confidence: 99%

“…To this end, we developed a bile acid injury assay compatible with high-content imaging based screening, coupled with automated image analysis of cellular features using a Cell Painting (Bray et al, 2016) style approach, followed by cell-level machine learning to characterize the perturbation of cells to a mix of primary and secondary bile-acids known to be present in humans (bile-acid mix (BAM)) (Nehra et al, 1999;Straub et al, 2019) see methods) (Figure 4A, Figure S5). First, we tested the individual and mixed bile-acids identified in human reflux (Straub et al, 2019) versus oxidative damage induced by Cumene hydroperoxide which has been shown to cause oxidative stress induced DNA damage in the esophagus (Peng et al, 2014(Peng et al, , 2021D. Ferrer-Torres et al, 2019).…”

Section: Human-derived Esophageal Basal-stem Cells Molecularly Resemble Native Tissuementioning

confidence: 99%

“…Genetic variations attributed to ancestry and racial background has also been implicated in various genetic diseases (i.e. sickle cell anemia (Kwiatkowski, 2005), cystic fibrosis (Knowles and Drumm, 2012), risk of EAC development (Ferrer-Torres et al ., 2019) and may lead to differences in response to therapeutic drugs (Ortega and Meyers, 2014; Hunter, 2020). Therefore, inclusion of individuals from diverse demographics for drug development and clinical trials is important for ensuring efficacy across the population.…”

Section: Introductionmentioning

confidence: 99%

“…Thus, failing to study racially/ancestrally and ethnically diverse populations will leave critical gaps in our understanding of variation to drug responses, and the effectiveness of new therapies. In the context of esophageal disease, genetic studies suggest racial differences in the tissue response to cell and DNA damage-inducing agents leading to carcinogenesis (Ferrer-Torres et al ., 2019); however, the ability to study racial disparities in esophageal disease has been hindered by the lack of diverse human models to study these mechanisms.…”

Section: Introductionmentioning

confidence: 99%

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In vitro models of the human esophagus reveal ancestrally diverse response to injury

Ferrer-Torres

et al. 2021

Preprint

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European Americans (EA) are more susceptible to esophageal tissue damage and inflammation when exposed to gastric acid and bile acid reflux and have a higher incidence of esophageal adenocarcinoma when compared to African Americans (AA). Population studies have implicated specific genes for these differences; however, the underlying cause for these differences is not well understood. We describe a robust long-term culture system to grow primary human esophagus in vitro, use single cell RNA sequencing to compare primary human biopsies to their in vitro counterparts, identify known and new molecular markers of basal cell types, and demonstrate that in vivo cellular heterogeneity is maintained in vitro. We further developed an ancestrally diverse biobank and a high-content, image based, screening assay to interrogate bile-acid injury response. These results demonstrated that AA esophageal cells responded significantly differently than EA-derived cells, mirroring clinical findings, having important implications for addressing disparities in early drug development pipelines.

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Proanthocyanidins mitigate bile acid‐induced changes in GSTT2 levels in a panel of racially diverse patient‐derived primary esophageal cell cultures

Weh

Turgeon

Rubenstein

et al. 2021

Molecular Carcinogenesis

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Persistent and symptomatic reflux of gastric and duodenal contents, known as gastroesophageal reflux disease (GERD), is the strongest risk factor for esophageal adenocarcinoma (EAC). Despite similar rates of GERD and other risk factors across racial groups, EAC progression disproportionately impacts Caucasians. We recently reported that elevated tissue levels of the detoxification enzyme GSTT2 in the esophagi of Blacks compared to Caucasians may contribute protection. Herein, we extend our research to investigate whether cranberry proanthocyanidins (C‐PAC) mitigate bile acid‐induced damage and GSTT2 levels utilizing a racially diverse panel of patient‐derived primary esophageal cultures. We have shown that C‐PACs mitigate reflux‐induced DNA damage through GSTT2 upregulation in a rat esophageal reflux model, but whether effects are recapitulated in humans or differentially based on race remains unknown. We isolated normal primary esophageal cells from Black and Caucasian patients and assessed GSTT2 protein levels and cellular viability following exposure to a bile acid cocktail with and without C‐PAC treatment. Constitutive GSTT2 levels were significantly elevated in Black (2.9‐fold) compared to Caucasian patients, as were GSTT2 levels in Black patients with GERD. C‐PAC treatment induced GSTT2 levels 1.6‐fold in primary normal esophageal cells. GSTT2 induction by C‐PAC was greatest in cells with constitutively low GSTT2 expression. Overall, C‐PAC mitigated bile‐induced reductions of GSTT2 and subsequent loss of cell viability regardless of basal GSTT2 expression or race. These data support that C‐PAC may be a safe efficacious agent to promote epithelial fitness through GSTT2 induction and in turn protect against bile acid‐induced esophageal injury.

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Constitutively Higher Level of GSTT2 in Esophageal Tissues From African Americans Protects Cells Against DNA Damage

Cited by 21 publications

References 39 publications

The antioxidant response in Barrett's tumorigenesis: A double-edged sword

The antioxidant response in Barrett's tumorigenesis: A double-edged sword

In vitro models of the human esophagus reveal ancestrally diverse response to injury

Proanthocyanidins mitigate bile acid‐induced changes in GSTT2 levels in a panel of racially diverse patient‐derived primary esophageal cell cultures

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