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Expression of metabolically targeted biomarkers in endometrial carcinoma
Heather Wahl1, Sayeema Daudi, Malti Kshirsagar
1Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, MI, USA.
Objectives:
The differential metabolic phenotype observed between malignant and non-transformed cells may constitute a biochemical basis for therapeutic intervention. Increased glucose uptake is one of the major metabolic changes found in malignant tumors, a process that is mediated by glucose transporters such as Glut1. Cellular growth can be regulated by mTOR in response to the nutrient milieu. In this study, we sought to determine if endometrial carcinoma cells express Glut1 and mTOR, and if inhibition of these factors is cytotoxic to endometrial carcinoma cells in vitro.
Methods:
Expression of Glut1, pAkt, and pmTOR was assessed in tissue microarrays constructed from 42 type I and 34 type II endometrial tumors by immunohistochemistry, and in a panel of endometrial carcinoma cell lines. Representative endometrial carcinoma cells with wild type or mutant endogenous PTEN were treated with the glucose analog 2-deoxyglucose (2-DG) and rapamycin, an mTOR inhibitor or cisplatin. Inhibition of cell growth and mechanism of cell death was determined.
Results:
Glut1, pAkt, and pmTOR were expressed strongly in both types I and II endometrial carcinoma. 2-DG and rapamycin induced apoptotic cell death in type I endometrial carcinoma cells, and profound growth inhibition and cytostasis in type II endometrial carcinoma cells.
Conclusions:
Glut1, pAkt, and pmTOR are overexpressed in endometrial carcinomas. Distinct alterations in the phosphatidylinositol 3'-kinase (PI3K) pathway upstream of mTOR, such as pAkt, may identify endometrial carcinoma patients who may benefit from adjuvant treatment with mTOR inhibitors and/or glucose analogs.
Insights
Endometrial carcinoma cells overexpress glucose transporter 1 (Glut1) and mTOR. Inhibiting these targets with 2-deoxyglucose (2-DG) or rapamycin shows potential for treating endometrial cancer.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Malignant cells exhibit altered metabolism, including increased glucose uptake via glucose transporters like Glut1.
- Mammalian target of rapamycin (mTOR) regulates cellular growth in response to nutrient availability.
- These metabolic changes present potential therapeutic targets in cancer treatment.
Purpose of the Study:
- To investigate the expression of Glut1 and mTOR in endometrial carcinoma.
- To determine the cytotoxic effects of inhibiting Glut1 and mTOR in endometrial carcinoma cells in vitro.
Main Methods:
- Immunohistochemistry was used to assess Glut1, pAkt, and pmTOR expression in endometrial tumor tissue microarrays and cell lines.
- Endometrial carcinoma cells were treated with 2-deoxyglucose (2-DG), rapamycin (an mTOR inhibitor), or cisplatin.
- Cell growth inhibition, cytostasis, and the mechanism of cell death were evaluated.
Main Results:
- Strong expression of Glut1, pAkt, and pmTOR was observed in both type I and type II endometrial carcinomas.
- Treatment with 2-DG and rapamycin induced apoptotic cell death in type I endometrial carcinoma cells.
- Profound growth inhibition and cytostasis were observed in type II endometrial carcinoma cells following treatment.
Conclusions:
- Glut1, pAkt, and pmTOR are overexpressed in endometrial carcinomas, indicating their potential role in tumorigenesis.
- Alterations in the phosphatidylinositol 3'-kinase (PI3K) pathway, such as elevated pAkt, may predict response to therapy.
- These findings suggest that targeting Glut1 and mTOR pathways could be a viable therapeutic strategy for endometrial cancer patients.