Research Article: High Glucose-Mediated STAT3 Activation in Endometrial Cancer Is Inhibited by Metformin: Therapeutic Implications for Endometrial Cancer

Date Published: January 23, 2017

Publisher: Public Library of Science

Author(s): John J. Wallbillich, Srirama Josyula, Uksha Saini, Roman A. Zingarelli, Kalpana Deepa Priya Dorayappan, Maria K. Riley, Ross A. Wanner, David E. Cohn, Karuppaiyah Selvendiran, Aamir Ahmad.


STAT3 is over-expressed in endometrial cancer, and diabetes is a risk factor for the development of type 1 endometrial cancer. We therefore investigated whether glucose concentrations influence STAT3 expression in type 1 endometrial cancer, and whether such STAT3 expression might be inhibited by metformin.

In Ishikawa (grade 1) endometrial cancer cells subjected to media with low, normal, or high concentrations of glucose, expression of STAT3 and its target proteins was evaluated by real-time quantitative PCR (qPCR). Ishikawa cells were treated with metformin and assessed with cell proliferation, survival, migration, and ubiquitin assays, as well as Western blot and qPCR. Expression of apoptosis proteins was evaluated with Western blot in Ishikawa cells transfected with a STAT3 overexpression plasmid and treated with metformin. A xenograft tumor model was used for studying the in vivo efficacy of metformin.

Expression of STAT3 and its target proteins was increased in Ishikawa cells cultured in high glucose media. In vitro, metformin inhibited cell proliferation, survival and migration but induced apoptosis. Metformin reduced expression levels of pSTAT3 ser727, total STAT3, and its associated cell survival and anti-apoptotic proteins. Additionally, metformin treatment was associated with increased degradation of pSTAT3 ser727. No change in apoptotic protein expression was noticed with STAT3 overexpression in Ishikawa cells. In vivo, metformin treatment led to a decrease in tumor weight as well as reductions of STAT3, pSTAT3 ser727, its target proteins.

These results suggest that STAT3 expression in type 1 endometrial cancer is stimulated by a high glucose environment and inhibited by metformin.

Partial Text

Endometrial cancer is the most common gynecologic cancer and the fourth-most common cancer among women in the United States. 60,050 new cases of endometrial cancer and 10,470 deaths due to the disease are estimated for 2016. The incidence of endometrial cancer has been rising, with a 2.3% annual increase reported from 2006–2012 [1]. This increase has been attributed to the most common subtype of endometrial cancer, type 1 [2]. Type 1 endometrial cancer is comprised of grades 1 and 2 endometrioid adenocarcinoma [3]. Risk factors for type 1 endometrial cancer include obesity and diabetes, which have been increasing in prevalence in the United States[4, 5]. Further, in women with endometrial cancer, obesity leads to a 6.25 fold increased risk of dying due to the disease [6].

The present study found that high glucose concentrations increase expression of STAT3 and its target proteins in grade 1 endometrial cancer cells. We also observed that metformin affects grade 1 endometrial cancer cell growth, apoptosis induction, and inhibits STAT3 and its target proteins in both in vitro and in vivo (with a murine xenograft model).




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