MAPK and PI3K Inhibition Reduces Proliferation of Barrett’s Adenocarcinoma in Vitro1

Vona-Davis, Linda; Frankenberry, Krista A.; Cunningham, Cynthia; Riggs, Dale R.; Jackson, Barbara; Szwerc, Michael F; McFadden, David W.

doi:10.1016/j.jss.2005.03.013

Cited by 16 publications

(17 citation statements)

References 17 publications

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“…To study the potential targets of Sorafenib's antiproliferative effects in SEG-1 cells, we first examined the effects of acid and TC on activating phosphorylations of ERK, p38 and Akt that are known to regulate proliferation, survival and G cyclins expression in Barrett's tissue and cancer cells [20][21][22][23][24][25][26][27]. Acid (pH 3.5) and TC (100 lM) caused significant increases in phosphoactive ERK, p38 and Akt.…”

Section: Resultsmentioning

confidence: 99%

“…Moreover, constituents of gastroesophageal refluxate, i.e., acid and bile acids modulate Barrett's cell proliferation and apoptosis increasing substantially the risk for EA [17,19]. We and others have previously pointed out the role of acid and bile acids to increase cell proliferation and survival in Barrett's cell line by up-regulating MAPK and PI3k/Akt signals [20][21][22][23][24][25][26][27]. The concomitant inductions of cyclin D1 and cyclin E in response to theses agents drive cell cycle progression through G1 to S transition [28][29][30].…”

Section: Introductionmentioning

confidence: 99%

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Sorafenib Triggers Antiproliferative and Pro-Apoptotic Signals in Human Esophageal Adenocarcinoma Cells

et al. 2008

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Sorafenib Triggers Antiproliferative and Pro-Apoptotic Signals in Human Esophageal Adenocarcinoma Cells

et al. 2008

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“…Bile reflux may also activate the extracellular regulated kinase (Erk) pathway, leading to cellular proliferation [6,7,8]. In vitro studies indicate that the antiapoptotic PI3 kinase/Akt pathway is also involved in the metaplasia-dysplasia-carcinoma sequence in EAC, and inhibition of this pathway reduces cell proliferation [9, 10]. However, there are limited in vivo data in this regard.…”

Section: Barrett’s Esophagusmentioning

confidence: 99%

“…Whether this association leads to an aggressive course in BE is unknown at this time[11]. Vona-Davis et al [10] reported that the combined inhibition of PI3 kinase and Erk reduces proliferation of cells derived from BE associated with EAC in vitro. A larger study in BE with the above biomarkers is warranted.…”

Section: Barrett’s Esophagusmentioning

confidence: 99%

Epidermal Growth Factor Receptor-Directed Therapy in Esophageal Cancer

Pande¹,

Iyer²,

Rani

et al. 2007

Oncology

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Esophageal adenocarcinoma (EAC) is one of the fastest growing malignancies in the US. The long-term survival of patients with this cancer remains poor; only 25% of patients undergoing surgical excision are alive after 5 years. Multimodal programs that incorporate radiotherapy, chemotherapy and surgery for localized tumors may result in a modest survival advantage. However, significant strides in this disease can result from the inclusion of targeted therapies. The epidermal growth factor receptor (EGFR) family represents one such target and is receiving increasing attention due to the advent of specific inhibitors. Studies conducted by us and others have shown that the overexpression of EGFR family signaling intermediates is common in Barrett’s esophagus and EAC. In the latter case, EGFR expression may have prognostic significance. EGFR inhibitors, including oral tyrosine kinase inhibitors and monoclonal antibodies, result in a synergistic antitumor effect with chemotherapeutic agents or with radiotherapy. Therefore, several ongoing studies include EGFR-directed therapy either alone or in combination with chemoradiotherapy for this disease. Our study of gefitinib, oxaliplatin and radiotherapy suggested that gefitinib can be safely incorporated into an oxaliplatin-based chemoradiation program for esophageal cancer, although the clinical activity of this combination is modest. Herein, we review the current literature on this subject.

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“…There are only limited data on Akt activation in BO: studies have suggested that gastrin-mediated proliferation in oesophageal adenocarcinoma and Barrett's oesophagus is Akt-dependant [12,13]. Pharmacological inhibition of phosphoinositol-3'kinase (PI3-kinase), which is a potential upstream activator of Akt, has been shown to reduce proliferation and induce apoptosis in cultured oesophageal cancer cell lines, without specifically examining the involvement of Akt [14]. There are no data concerning Akt activation in the Barrett's metaplasia-carcinoma sequence.…”

Section: Introductionmentioning

confidence: 99%

Activation of Akt is increased in the dysplasia-carcinoma sequence in Barrett's oesophagus and contributes to increased proliferation and inhibition of apoptosis: a histopathological and functional study

et al. 2007

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BackgroundThe incidence of oesophageal adenocarcinoma is increasing rapidly in the developed world. The serine-threonine protein kinase and proto-oncogene Akt has been reported to regulate proliferation and apoptosis in several tissues but there are no data on the involvement of Akt in oesophageal carcinogenesis. Therefore we have examined the activation of Akt in Barrett's oesophagus and oesophageal adenocarcinoma and the functional effects of Akt activation in vitro.MethodsExpression of total and active (phosphorylated) Akt were determined in endoscopic biopsies and surgical resection specimens using immunohistochemistry. The functional effects of Akt were examined using Barrett's adenocarcinoma cells in culture.ResultsIn normal squamous oesophagus, erosive oesophagitis and non-dysplastic Barrett's oesophagus, phospho-Akt was limited to the basal 1/3 of the mucosa. Image analysis confirmed that Akt activation was significantly increased in non-dysplastic Barrett's oesophagus compared to squamous epithelium and further significantly increased in high-grade dysplasia and adenocarcinoma. In all cases of high grade dysplasia and adenocarcinoma Akt was activated in the luminal 1/3 of the epithelium. Transient acid exposure and the obesity hormone leptin activated Akt, stimulated proliferation and inhibited apoptosis: the combination of acid and leptin was synergistic. Inhibition of Akt phosphorylation with LY294002 increased apoptosis and blocked the effects of acid and leptin both alone and in combination. Activation of Akt was associated with downstream phosphorylation and deactivation of the pro-apoptotic protein Bad and phosphorylation of the Forkhead family transcription factor FOXO1.ConclusionAkt is abnormally activated in Barrett's oesophagus, high grade dysplasia and adenocarcinoma. Akt activation promotes proliferation and inhibits apoptosis in Barrett's adenocarcinoma cells and both transient acid exposure and leptin stimulate Akt phosphorylation. Downstream targets of Akt include Bad and Forkhead transcription factors. Activation of Akt in obesity and by reflux of gastric acid may be important in the pathogenesis of Barrett's adenocarcinoma

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MAPK and PI3K Inhibition Reduces Proliferation of Barrett’s Adenocarcinoma in Vitro1

Cited by 16 publications

References 17 publications

Sorafenib Triggers Antiproliferative and Pro-Apoptotic Signals in Human Esophageal Adenocarcinoma Cells

Sorafenib Triggers Antiproliferative and Pro-Apoptotic Signals in Human Esophageal Adenocarcinoma Cells

Epidermal Growth Factor Receptor-Directed Therapy in Esophageal Cancer

Activation of Akt is increased in the dysplasia-carcinoma sequence in Barrett's oesophagus and contributes to increased proliferation and inhibition of apoptosis: a histopathological and functional study

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