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Salicylketoximes That Target Glucose Transporter?1 Restrict Energy Supply to Lung Cancer Cells.

ABSTRACT: The glucose transporter GLUT1 is frequently overexpressed in most tumor tissues because rapidly proliferating cancer cells rely primarily on glycolysis, a low-efficiency metabolic pathway that necessitates a very high rate of glucose consumption. Because blocking GLUT1 is a promising anticancer strategy, we developed a novel class of GLUT1 inhibitors based on the 4-aryl-substituted salicylketoxime scaffold. Some of these compounds are efficient inhibitors of glucose uptake in lung cancer cells and have a notable antiproliferative effect. In contrast to their 5-aryl-substituted regioisomers, the newly synthesized compounds reported herein do not display significant binding to the estrogen receptors. The inhibition of glucose uptake in cancer cells by these compounds was further observed by fluorescence microscopy imaging using a fluorescent analogue of glucose. Therefore, blocking the ability of tumor cells to take up glucose by means of these small molecules, or by further optimized derivatives, may be a successful approach in the development of novel anticancer drugs.

SUBMITTER: Granchi C

PROVIDER: S-EPMC4743644 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Salicylketoximes That Target Glucose Transporter 1 Restrict Energy Supply to Lung Cancer Cells.

Granchi Carlotta C Qian Yanrong Y Lee Hyang Yeon HY Paterni Ilaria I Pasero Carolina C Iegre Jessica J Carlson Kathryn E KE Tuccinardi Tiziano T Chen Xiaozhuo X Katzenellenbogen John A JA Hergenrother Paul J PJ Minutolo Filippo F

ChemMedChem 20150901 11

The glucose transporter GLUT1 is frequently overexpressed in most tumor tissues because rapidly proliferating cancer cells rely primarily on glycolysis, a low-efficiency metabolic pathway that necessitates a very high rate of glucose consumption. Because blocking GLUT1 is a promising anticancer strategy, we developed a novel class of GLUT1 inhibitors based on the 4-aryl-substituted salicylketoxime scaffold. Some of these compounds are efficient inhibitors of glucose uptake in lung cancer cells a ...[more]

PMID: 26332543

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Project description:BackgroundLoss-of-function mutations or abnormal expressions of E ubiquitin ligases contributes to tumorigenesis. TRIM38 was reported to regulate immunity, inflammatory responses or apoptosis, but its roles in tumor progression remain inconclusive. This study aimed to investigate the functional roles of TRIM38 in bladder cancer to identify effective targets.MethodsFirstly, the expression data of ubiquitination-associated genes were derived from the TCGA-BLCA cohort. Univariate Cox regression method was utilized to screen prognostic genes. Colony formation assay, Transwell assay, sphere formation assays were used to assess functional roles of TRIM38. TAP/MS assay was used to identify downstream substrates of TRIM38. Fresh clinical BLCA tissues were collected to evaluate the clinicopathological features of patients with different TRIM38 expression. The subcutaneous tumor models were established to determine the drug efficacy of BAY-876.ResultsA list of ubiquitination-associated signature was identified based on the screening in TCGA-BLCA cohort. Subsequent validations revealed that TRIM38 was a significant suppressor in tumors, which was expressed lowly in BLCA. Kaplan-Meier analysis and correlation analysis suggested that patients with low TRIM38 expressions had shorter survival time and advanced clinical characteristics. Targeting TRIM38 reinforced BLCA cells proliferation, migration and stemness. Mechanistically, TRIM38 interacted with GLUT1, thereby promoting its ubiquitinoylation and degradation. Furthermore, TRIM38 deficiency relied on accumulated GLUT1 proteins to enhance BLCA malignant features and cellular glycolytic capacity. We accordingly investigated the efficacy of GLUT1 inhibitor (BAY-876) in BLCA and determined its IC50 values across cell lines. Tumor xenograft models further validated that BAY-876 could effectively suppress the in vivo growth of TRIM38low/- BLCA.ConclusionsOur results suggested that TRIM38 plays a tumor suppressive role in BLCA pathogenesis and TRIM38/GLUT1 axis is a therapeutic vulnerability for clinical treatment, which possessing great translational significance.

Project description:This work joins a series that methodically tests the predictions of the Selfish-Brain theory. The theory postulates a vital ability of the mammalian brain, namely to give priority to its own energy metabolism. The brain behaves "selfishly" in this respect. For the cerebral artery occlusion studied here, the theory predicts an increase in blood glucose concentration, what becomes the hypothesis to be tested. We conducted a systematic review of cerebral-artery-occlusion papers to test whether or not the included studies could confirm this hypothesis. We identified 239 records, screened 231 works by title or abstract, and analyzed 89 by full text. According to strict selection criteria (set out in our PROSPERO preregistration, complying with PRISMA guidelines), 7 papers provided enough information to decide on the hypothesis. Our hypothesis could be fully confirmed for the 3 to 24 h after the onset of a transient 2 h or permanent occlusion. As for the mechanism, the theory predicts that the energy-deprived brain suppresses insulin secretion via the sympathoadrenal system, thereby preventing insulin-mediated glucose uptake into muscle and fat and, as a result, enhancing insulin-independent glucose uptake via the blood-brain barrier. Evidence from our included studies actually demonstrated cerebral insulin suppression. In all, the current work confirms the second major prediction of the Selfish-Brain theory that relates to a proximal bottleneck of the cerebral supply chain, cerebral artery occlusion. Its first major prediction relates to a distal supply bottleneck, caloric restriction, and is fulfilled as shown by our previous work, whereas the prediction of the long held gluco-lipostatic theory, which sees the brain as only passively supplied, is violated (Sprengell et al., 2021). The crucial point was that caloric restriction elicits smaller changes in mass (energy) in the brain than in the body. Taken together, the evidence from the current and previous work clearly shows that the most accurate predictions are possible with a theory that views the brain as an independently self-regulating energy compartment occupying a primary position in energy metabolism.

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Salicylketoximes That Target Glucose Transporter?1 Restrict Energy Supply to Lung Cancer Cells.

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Salicylketoximes That Target Glucose Transporter 1 Restrict Energy Supply to Lung Cancer Cells.

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