Metabolic Vulnerabilities in Endometrial Cancer

Byrne, Frances L.; Poon, Ivan K. H.; Modesitt, Susan C.; Tomsig, Jose L.; Chow, Jenny D.Y.; Healy, Marin E.; Baker, Wendy; Atkins, Kristen A.; Lancaster, Johnathan M.; Marchion, Douglas C.; Moley, Kelle H.; Ravichandran, Kodi S.; Slack‐Davis, Jill K.; Hoehn, Kyle L.

doi:10.1158/0008-5472.can-14-0254

Cited by 87 publications

(83 citation statements)

References 48 publications

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“…Class I GLUTs (GLUTs 1-4) are glucose transporters; Class II GLUTs (GLUTs 5, 7, 9 and 11) are fructose transporters; and Class III GLUTs (GLUTs 6, 8, 10, 12 and HMIT1) are structurally atypical members of the GLUT family, which are poorly defined at present. Recent studies confirmed that GLUTs (GLUT1, GLUT3 and GLUT6) are upregulated in the malignant endometrium compared with nonmalignant counterparts [27,28]. In this study, a high level of GLUT4 was observed in the UEC tissues.…”

Section: Discussionsupporting

confidence: 80%

High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion

Gu¹,

Xie²,

Zhang³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Uterus endometrial cancer (UEC) is the common malignancy among gynecologic cancers, and most of them are type I estrogen-dependent UEC. Diabetes is well-known risk factor for the development of UEC. However, the underlying link between high glucose (HG) and the estrogen receptor in UEC remains unclear. Epithelial-mesenchymal transition (EMT) has also been shown to occur during the initiation of metastasis in cancer progression. The aim of this study was to determine the relationships and roles of HG, estrogen receptor and EMT in the growth and migration of UEC. Methods: The expression of glucose transport protein 4 (GLUT4) in the control endometrium and UEC tissues was detected by immunohistochemistry (IHC); the cell viability and invasion were analyzed through CCK-8 and Matrigel invasion assays; the transcriptional level of EMT-related genes was evaluated through real-time PCR; and the effect of HG and / or GLUT4 on estrogen receptors, vascular endothelial growth factor (VEGF) and its receptor VEGFR was analyzed through western blotting, ELISA and flow cytometry (FCM) assay, respectively. In addition, Ishikawa-xenografted nude mice were constructed and were used to analyze the effect of estrogen and GLUT4 on the growth of UEC in vivo. Results: Here, we found that exposure to HG led to a high level of viability and invasion of UEC cell lines (UECC, Ishikawa and RL95-2 cells). Compared with the normal endometrium, a higher level of GLUT4 was observed in UEC tissues. Silencing GLUT4 obviously inhibited the HG-promoted viability, invasion and expression of EMT-related genes (TWIST, SNAIL and CTNNB1) of UECC promoted by HG. Further analysis showed that HG and GLUT4 promoted the secretion of VEGF and expression of VEGFR in UECC. Treatment with HG led to the increase of estrogen receptor α (ERα) and β (ERβ) in UECC, blocking ERα or ERβ resulted in the decreases in GLUT4 expression, TWIST, SNAIL and CTNNB1 transcription, and VEGF and VEGFR expression in UECC. Treatment with anti-human VEGF neutralizing antibody restricted the viability and invasion of UECC that was induced by HG and estrogen. Exposure to estrogen accelerated growth, VEGF production, and TWIST and CTNNB1 expression in UEC in Ishikawa-xenografted nude mice, and silencing GLUT4 restricted these effects. Conclusion: These data suggest that HG increases GLUT4 and VEGF/VEGFR expression, further promotes EMT process and accelerates the development of UEC by up-regulating ER

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Section: Discussionsupporting

confidence: 80%

High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion

Gu¹,

Xie²,

Zhang³

et al. 2018

Cell Physiol Biochem

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“…Lipogenesis assays were performed according to methods previously established in our laboratory39. In brief, assays were performed on monolayered cells in Krebs-Ringer Phosphate buffer supplemented with non-labelled substrates: 5 mM glucose, 0.5 mM glutamine, 125 μM palmitate, 50 μM acetate and 1 mM carnitine with addition of either 5 μCi ml −1 14 C-glucose or 10 μCi ml −1 14 C-acetate.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival

et al. 2017

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The metabolic pathway of de novo lipogenesis is frequently upregulated in human liver tumours, and its upregulation is associated with poor prognosis. Blocking lipogenesis in cultured liver cancer cells is sufficient to decrease cell viability; however, it is not known whether blocking lipogenesis in vivo can prevent liver tumorigenesis. Herein, we inhibit hepatic lipogenesis in mice by liver-specific knockout of acetyl-CoA carboxylase (ACC) genes and treat the mice with the hepatocellular carcinogen diethylnitrosamine (DEN). Unexpectedly, mice lacking hepatic lipogenesis have a twofold increase in tumour incidence and multiplicity compared to controls. Metabolomics analysis of ACC-deficient liver identifies a marked increase in antioxidants including NADPH and reduced glutathione. Importantly, supplementing primary wild-type hepatocytes with glutathione precursors improves cell survival following DEN treatment to a level indistinguishable from ACC-deficient primary hepatocytes. This study shows that lipogenesis is dispensable for liver tumorigenesis in mice treated with DEN, and identifies an important role for ACC enzymes in redox regulation and cell survival.

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“…In addition, in multiple myeloma (MM) cells, in which HK-II was over-expressed, 3-BP promptly and substantially suppressed adenosine triphosphate production and induced cell death [63]. For endometrial cancer, 3-BP induced tumor necrosis in vitro and inhibited tumor growth in vivo [64]. It has also been reported that 3-BP induced apoptosis in MDA-MB-231 breast cancer cells by downregulating Mcl-1 through the PI3K/Akt signaling pathway, which is upstream of HK-II [65].…”

Section: Agents Targeted Inhibiting the Hk-ii-mediated Warburg Effectmentioning

confidence: 99%

Warburg effect, hexokinase-II, and radioresistance of laryngeal carcinoma

Zhong

Zhou

2016

Oncotarget

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Radiotherapy is now widely used as a part of multidisciplinary treatment approaches for advanced laryngeal carcinoma and preservation of laryngeal function. However, the mechanism of the radioresistance is still unclear. Some studies have revealed that the Warburg effect promotes the radioresistance of various malignant tumors, including laryngeal carcinoma. Among the regulators involved in the Warburg effect, hexokinase-II (HK-II) is a crucial glycolytic enzyme that catalyzes the first essential step of glucose metabolism. HK-II is reportedly highly expressed in some human solid carcinomas by many studies. But for laryngeal carcinoma, there is only one. Till now, no studies have directly targeted inhibited HK-II and enhanced the radiosensitivity of laryngeal carcinoma. Accumulating evidence has shown that dysregulated signaling pathways often result in HK-II overexpression. Here, we summarize recent advances in understanding the association among the Warburg effect, HK-II, and the radioresistance of laryngeal carcinoma. We speculate on the feasibility of enhancing radiosensitivity by targeted inhibiting HK-II signaling pathways in laryngeal carcinoma, which may provide a novel anticancer therapy.

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Metabolic Vulnerabilities in Endometrial Cancer

Cited by 87 publications

References 48 publications

High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion

High Glucose Promotes Epithelial-Mesenchymal Transition of Uterus Endometrial Cancer Cells by Increasing ER/GLUT4-Mediated VEGF Secretion

Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival

Warburg effect, hexokinase-II, and radioresistance of laryngeal carcinoma

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