Metabolic control of cancer progression as novel targets for therapy

Talukdar, Sarmistha; Emdad, Luni; Gogna, Rajan; Das, Swadesh K.; Fisher, Paul B.

doi:10.1016/bs.acr.2021.06.002

Cited by 5 publications

(3 citation statements)

References 277 publications

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“…Metabolism is an important part of tumorigenesis as well as the progression of cancer [ 46 – 48 ]. M 4 N combination treatment with TMZ suppressed both the conversion from pyruvate to lactate by LDHA, the last enzymatic reaction of glycolysis, and the TCA cycle in LN229 tumors ( Fig 3A ).…”

Section: Discussionmentioning

confidence: 99%

Tetra-O-methyl-nordihydroguaiaretic acid inhibits energy metabolism and synergistically induces anticancer effects with temozolomide on LN229 glioblastoma tumors implanted in mice while preventing obesity in normal mice that consume high-fat diets

et al. 2023

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Tetra-O-methyl-nordihydroguaiaretic acid (terameprocol; M4N), a global transcription inhibitor, in combination with a second anticancer drug induces strong tumoricidal activity and has the ability to suppress energy metabolism in cultured cancer cells. In this study, we showed that after continuous oral consumption of high-fat (HF) diets containing M4N, the M4N concentration in most of the organs in mice reached ~1 μM (the M4N concentration in intestines and fat pads was as high as 20–40 μM) and treatment with the combination of M4N with temozolomide (TMZ) suppressed glycolysis and the tricarboxylic acid cycle in LN229 human glioblastoma implanted in xenograft mice. Combination treatment of M4N with TMZ also reduced the levels of lactate dehydrogenase A (LDHA), a key enzyme for glycolysis; lactate, a product of LDHA-mediated enzymatic activity; nicotinamide phosphoribosyltransferase, a rate-limiting enzyme for nicotinamide adenine dinucleotide plus hydrogen (NADH)/NAD+ salvage pathway; and NAD+, a redox electron carrier essential for energy metabolism. It was also shown that M4N suppressed oxygen consumption in cultured LN229 cells, indicating that M4N inhibited oxidative phosphorylation. Treatment with M4N and TMZ also decreased the level of hypoxia-inducible factor 1A, a major regulator of LDHA, under hypoxic conditions. The ability of M4N to suppress energy metabolism resulted in induction of the stress-related proteins activating transcription factor 4 and cation transport regulator-like protein 1, and an increase in reactive oxygen species production. In addition, the combination treatment of M4N with TMZ reduced the levels of oncometabolites such as 2-hydroxyglutarate as well as the aforementioned lactate. M4N also induced methylidenesuccinic acid (itaconate), a macrophage-specific metabolite with anti-inflammatory activity, in tumor microenvironments. Meanwhile, the ability of M4N to suppress energy metabolism prevented obesity in mice consuming HF diets, indicating that M4N has beneficial effects on normal tissues. The dual ability of combination treatment with M4N to suppress both energy metabolism and oncometabolites shows that it is potentially an effective therapy for cancer.

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Section: Discussionmentioning

confidence: 99%

Tetra-O-methyl-nordihydroguaiaretic acid inhibits energy metabolism and synergistically induces anticancer effects with temozolomide on LN229 glioblastoma tumors implanted in mice while preventing obesity in normal mice that consume high-fat diets

et al. 2023

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“…The TME supports the intricate process of tumorigenesis by modulating various functionally interlinked cells and non-cellular components ( 14 , 15 ). Numerous previous studies have reported modulation function of immune and inflammatory cells on UCEC cells.…”

Section: Introductionmentioning

confidence: 98%

Inflammation-Related LncRNAs Signature for Prognosis and Immune Response Evaluation in Uterine Corpus Endometrial Carcinoma

Song

Chen

et al. 2022

Front. Oncol.

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BackgroundsUterine corpus endometrial carcinoma (UCEC) is one of the greatest threats on the female reproductive system. The aim of this study is to explore the inflammation-related LncRNA (IRLs) signature predicting the clinical outcomes and response of UCEC patients to immunotherapy and chemotherapy.MethodsConsensus clustering analysis was employed to determine inflammation-related subtype. Cox regression methods were used to unearth potential prognostic IRLs and set up a risk model. The prognostic value of the prognostic model was calculated by the Kaplan-Meier method, receiver operating characteristic (ROC) curves, and univariate and multivariate analyses. Differential abundance of immune cell infiltration, expression levels of immunomodulators, the status of tumor mutation burden (TMB), the response to immune checkpoint inhibitors (ICIs), drug sensitivity, and functional enrichment in different risk groups were also explored. Finally, we used quantitative real-time PCR (qRT-PCR) to confirm the expression patterns of model IRLs in clinical specimens.ResultsAll UCEC cases were divided into two clusters (C1 = 454) and (C2 = 57) which had significant differences in prognosis and immune status. Five hub IRLs were selected to develop an IRL prognostic signature (IRLPS) which had value in forecasting the clinical outcome of UCEC patients. Biological processes related to tumor and immune response were screened. Function enrichment algorithm showed tumor signaling pathways (ERBB signaling, TGF-β signaling, and Wnt signaling) were remarkably activated in high-risk group scores. In addition, the high-risk group had a higher infiltration level of M2 macrophages and lower TMB value, suggesting patients with high risk were prone to a immunosuppressive status. Furthermore, we determined several potential molecular drugs for UCEC.ConclusionWe successfully identified a novel molecular subtype and inflammation-related prognostic model for UCEC. Our constructed risk signature can be employed to assess the survival of UCEC patients and offer a valuable reference for clinical treatment regimens.

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“…In recent studies, it has been shown that tumor cells can escape immune surveillance due to an accumulation of lactic acid ( 8 , 9 ). An increasing number of studies have aimed to explore the actual link between metabolic processes and oncogenesis ( 10 ), and pharmacological agents targeting critical regulators of glucose metabolism are in development ( 11 , 12 ). It is well known that transcription factors are critical in regulating the Warburg effect ( 13 ), including p53 , MYC , and HIF-1 α which are responsible for the metabolic switch from oxidative phosphorylation to the glycolysis pathway in tumor cells.…”

Section: Introductionmentioning

confidence: 99%

BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming

Xie¹,

Feng²,

Fan³

et al. 2022

Transl Lung Cancer Res

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Background: Metabolic reprogramming is an emerging cancer feature that has recently drawn special attention since it promotes tumor cell growth and proliferation. However, the mechanism of the Warburg effect is still largely unknown. This research aimed to reveal the effects of BarH-like homeobox 2 (BARX2) in regulating tumor progression and glucose metabolism in lung adenocarcinoma (LUAD).Methods: Expression of BARX2 was measured by quantitative real-time polymerase chain reaction (qRT-PCR) in LUAD cell line and tissues, and the tumor-promoting function of BARX2 in LUAD cells was detected in vitro and in vivo xenograft models. The metabolic effects of BARX2 were examined by detecting glucose uptake, the production levels of lactate and pyruvate, and the extracellular acidification rate (ECAR).Chromatin immunoprecipitation (ChIP) assay and luciferase reporter gene assay were used to identify the underlying molecular mechanism of BARX2 regulation of HK2. Further studies showed that transcription factor FOXA1 directly interacts with BARX2 and promotes the transcriptional activity of BARX2.Results: BARX2 was remarkably up-regulated in LUAD tissues and positively linked to advanced clinical stage and poor prognosis. In vitro and in vivo data indicated ectopic expression of BARX2 enhanced cell proliferation and tumorigenesis, whereas BARX2 knockdown suppressed these effects. Metabolic-related experiments showed BARX2 promoted the reprogramming of glucose metabolism. Mechanistically, the BARX2/FOXA1/HK2 axis promoted LUAD progression and energy metabolism reprogramming.Conclusions: In summary, our research first defined BARX2 as a tumor-promoting factor in LUAD and that it may act as a novel prognostic biomarker and new therapeutic target for the disease.

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Metabolic control of cancer progression as novel targets for therapy

Cited by 5 publications

References 277 publications

Tetra-O-methyl-nordihydroguaiaretic acid inhibits energy metabolism and synergistically induces anticancer effects with temozolomide on LN229 glioblastoma tumors implanted in mice while preventing obesity in normal mice that consume high-fat diets

Tetra-O-methyl-nordihydroguaiaretic acid inhibits energy metabolism and synergistically induces anticancer effects with temozolomide on LN229 glioblastoma tumors implanted in mice while preventing obesity in normal mice that consume high-fat diets

Inflammation-Related LncRNAs Signature for Prognosis and Immune Response Evaluation in Uterine Corpus Endometrial Carcinoma

BARX2/FOXA1/HK2 axis promotes lung adenocarcinoma progression and energy metabolism reprogramming

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