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15 pages, 3073 KiB

Open AccessFeature PaperArticle

Liver X Receptor Inverse Agonist GAC0001E5 Impedes Glutaminolysis and Disrupts Redox Homeostasis in Breast Cancer Cells

by Asitha Premaratne, Charles Ho, Shinjini Basu, Ashfia Fatima Khan, Tasneem Bawa-Khalfe and Chin-Yo Lin

Biomolecules 2023, 13(2), 345; https://doi.org/10.3390/biom13020345 - 10 Feb 2023

Viewed by 2302

Abstract

Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors which regulate the expression of lipid and cholesterol metabolism genes. Moreover, LXRs and their ligands have been shown to inhibit tumor growth in a variety of cancers. We [...] Read more.

Liver X receptors (LXRs) are members of the nuclear receptor family of ligand-dependent transcription factors which regulate the expression of lipid and cholesterol metabolism genes. Moreover, LXRs and their ligands have been shown to inhibit tumor growth in a variety of cancers. We have previously identified the small molecule compound GAC0001E5 (1E5) as an LXR inverse agonist and a potent inhibitor of pancreatic cancer cells. Transcriptomic and metabolomic studies showed that 1E5 disrupts glutamine metabolism, an essential metabolic pathway commonly reprogrammed during malignant transformation, including in breast cancers. To determine the role of LXRs and potential application of 1E5 in breast cancer, we examined LXR expression in publicly available clinical samples, and found that LXR expression is elevated in breast tumors as compared to normal tissues. In luminal A, endocrine therapy-resistant, and triple-negative breast cancer cells, 1E5 exhibited LXR inverse agonist and “degrader” activity and strongly inhibited cell proliferation and colony formation. Treatments with 1E5 downregulated the transcription of key glutaminolysis genes, and, correspondingly, biochemical assays indicated that 1E5 lowered intracellular glutamate and glutathione levels and increased reactive oxygen species. These results indicate that novel LXR ligand 1E5 is an inhibitor of glutamine metabolism and redox homeostasis in breast cancers and suggest that modulating LXR activity and expression in tumor cells is a promising strategy for targeting metabolic reprogramming in breast cancer therapeutics. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies II)

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17 pages, 4030 KiB

Open AccessEditor’s ChoiceArticle

Alteration of Cellular Energy Metabolism through LPAR2-Axin2 Axis in Gastric Cancer

by Hosne Ara, Utsab Subedi, Papori Sharma, Susmita Bhattarai, Sudha Sharma, Shrivats Manikandan, Xiuping Yu, Md. Shenuarin Bhuiyan, Hong Sun, Sumitra Miriyala and Manikandan Panchatcharam

Biomolecules 2022, 12(12), 1805; https://doi.org/10.3390/biom12121805 - 02 Dec 2022

Cited by 3 | Viewed by 2151

Abstract

Lysophosphatidic acid (LPA), a multifunctional endogenous phospholipid, plays a vital role in cellular homeostasis and the malignant behavior of cancer cells through G-protein-coupled receptors. However, the role of LPA in β-catenin-mediated gastric cancer is unknown. Here, we have noted the high expression of [...] Read more.

Lysophosphatidic acid (LPA), a multifunctional endogenous phospholipid, plays a vital role in cellular homeostasis and the malignant behavior of cancer cells through G-protein-coupled receptors. However, the role of LPA in β-catenin-mediated gastric cancer is unknown. Here, we have noted the high expression of LPAR2 in human gastric cancer tissues, and that LPA treatment significantly increased the proliferation, migration, and invasion of human gastric cancer cells. Results from our biochemical experiments showed that an LPA exposure increased the expression of β-catenin and its nuclear localization, increased the phosphorylation of glycogen synthase kinase 3β (GSK-3β), decreased the expression of Axin2, and increased the expression of the target genes of the β-catenin signaling pathway. The LPA2 receptor (LPAR2) antagonist significantly reduced the LPA-induced nuclear localization of β-catenin, the primary signaling event. The knockdown of LPAR2 in the gastric cancer cell lines robustly reduced the LPA-induced β-catenin activity. An LPA exposure increased the ATP production by both oxidative phosphorylation and glycolysis, and this effect was abrogated with the addition of an LPAR2 antagonist and XAV393, which stabilizes the Axin and inhibits the β-catenin signaling pathway. Based on our findings, the possibility that LPA contributes to gastric cancer initiation and progression through the β-catenin signaling pathway as well as by the dysregulation of the energy metabolism via the LPAR2 receptor and Axin2, respectively, provides a novel insight into the mechanism of and possible therapeutic targets of gastric cancer. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies II)

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14 pages, 1650 KiB

Open AccessArticle

Statins Alleviate Tumor Hypoxia in Prostate Cancer Models by Decreasing Oxygen Consumption: An Opportunity for Radiosensitization?

by Donatienne d’Hose, Lionel Mignion, Loïc Hamelin, Pierre Sonveaux, Bénédicte F. Jordan and Bernard Gallez

Biomolecules 2022, 12(10), 1418; https://doi.org/10.3390/biom12101418 - 03 Oct 2022

Cited by 4 | Viewed by 1507

Abstract

Background: Because statins were found to decrease the oxygen consumption rate (OCR) of a variety of normal cells, our hypothesis was that statins may also decrease the OCR of cancer cells, alleviate tumor hypoxia and radiosensitize tumors. Methods: OCR was assessed using the [...] Read more.

Background: Because statins were found to decrease the oxygen consumption rate (OCR) of a variety of normal cells, our hypothesis was that statins may also decrease the OCR of cancer cells, alleviate tumor hypoxia and radiosensitize tumors. Methods: OCR was assessed using the Seahorse XF96 technology and EPR respirometry in PC-3 prostate cancer cells. Mitochondrial superoxide production was measured by EPR with mitoTEMPO-H as a sensing probe. Tumor pO₂ was measured in vivo using low-frequency EPR oximetry to define the optimal window of reoxygenation, the time at which tumors were irradiated with a single 6 Gy dose with a Cesium-137 irradiator. Results: 24-h exposure to simvastatin and fluvastatin significantly decreased the OCR of PC-3 cancer cells. An increase in mitochondrial superoxide levels was also observed after fluvastatin exposure. The PC-3 prostate cancer model was found highly hypoxic at the basal level. When mice were treated with simvastatin or fluvastatin (daily injection of 20 mg/kg), tumor oxygenation increased 48 and 72 h after initiation of the treatment. However, despite reoxygenation, simvastatin did not sensitize the PC-3 tumor model to RT. Conclusions: exposure to statins affect tumor metabolism and tumor oxygenation, however, with limited impact on tumor growth with or without irradiation. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies II)

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20 pages, 3086 KiB

Open AccessEditor’s ChoiceArticle

Altered L-Arginine Metabolic Pathways in Gastric Cancer: Potential Therapeutic Targets and Biomarkers

by Iwona Bednarz-Misa, Mariusz G. Fleszar, Paulina Fortuna, Łukasz Lewandowski, Magdalena Mierzchała-Pasierb, Dorota Diakowska and Małgorzata Krzystek-Korpacka

Biomolecules 2021, 11(8), 1086; https://doi.org/10.3390/biom11081086 - 23 Jul 2021

Cited by 14 | Viewed by 3586

Abstract

There is a pressing need for molecular targets and biomarkers in gastric cancer (GC). We aimed at identifying aberrations in L-arginine metabolism with therapeutic and diagnostic potential. Systemic metabolites were quantified using mass spectrometry in 293 individuals and enzymes’ gene expression was quantified [...] Read more.

There is a pressing need for molecular targets and biomarkers in gastric cancer (GC). We aimed at identifying aberrations in L-arginine metabolism with therapeutic and diagnostic potential. Systemic metabolites were quantified using mass spectrometry in 293 individuals and enzymes’ gene expression was quantified in 29 paired tumor-normal samples using qPCR and referred to cancer pathology and molecular landscape. Patients with cancer or benign disorders had reduced systemic arginine, citrulline, and ornithine and elevated symmetric dimethylarginine and dimethylamine. Citrulline and ornithine depletion was accentuated in metastasizing cancers. Metabolite diagnostic panel had 91% accuracy in detecting cancer and 70% accuracy in differentiating cancer from benign disorders. Gastric tumors had upregulated NOS2 and downregulated ASL, PRMT2, ORNT1, and DDAH1 expression. NOS2 upregulation was less and ASL downregulation was more pronounced in metastatic cancers. Tumor ASL and PRMT2 expression was inversely related to local advancement. Enzyme up- or downregulation was greater or significant solely in cardia subtype. Metabolic reprogramming in GC includes aberrant L-arginine metabolism, reflecting GC subtype and pathology, and is manifested by altered interplay of its intermediates and enzymes. Exploiting L-arginine metabolic pathways for diagnostic and therapeutic purposes is warranted. Functional studies on ASL, PRMT2, and ORNT1 in GC are needed. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies II)

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Review

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70 pages, 8544 KiB

Open AccessReview

The Interplay between Dysregulated Metabolism and Epigenetics in Cancer

by Mahmoud Adel Bassal

Biomolecules 2023, 13(6), 944; https://doi.org/10.3390/biom13060944 - 05 Jun 2023

Cited by 1 | Viewed by 2615

Abstract

Cellular metabolism (or energetics) and epigenetics are tightly coupled cellular processes. It is arguable that of all the described cancer hallmarks, dysregulated cellular energetics and epigenetics are the most tightly coregulated. Cellular metabolic states regulate and drive epigenetic changes while also being capable [...] Read more.

Cellular metabolism (or energetics) and epigenetics are tightly coupled cellular processes. It is arguable that of all the described cancer hallmarks, dysregulated cellular energetics and epigenetics are the most tightly coregulated. Cellular metabolic states regulate and drive epigenetic changes while also being capable of influencing, if not driving, epigenetic reprogramming. Conversely, epigenetic changes can drive altered and compensatory metabolic states. Cancer cells meticulously modify and control each of these two linked cellular processes in order to maintain their tumorigenic potential and capacity. This review aims to explore the interplay between these two processes and discuss how each affects the other, driving and enhancing tumorigenic states in certain contexts. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies II)

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24 pages, 853 KiB

Open AccessFeature PaperEditor’s ChoiceReview

One-Carbon and Polyamine Metabolism as Cancer Therapy Targets

by Anowarul Islam, Zeeshan Shaukat, Rashid Hussain and Stephen L. Gregory

Biomolecules 2022, 12(12), 1902; https://doi.org/10.3390/biom12121902 - 19 Dec 2022

Cited by 4 | Viewed by 3256

Abstract

Cancer metabolic reprogramming is essential for maintaining cancer cell survival and rapid replication. A common target of this metabolic reprogramming is one-carbon metabolism which is notable for its function in DNA synthesis, protein and DNA methylation, and antioxidant production. Polyamines are a key [...] Read more.

Cancer metabolic reprogramming is essential for maintaining cancer cell survival and rapid replication. A common target of this metabolic reprogramming is one-carbon metabolism which is notable for its function in DNA synthesis, protein and DNA methylation, and antioxidant production. Polyamines are a key output of one-carbon metabolism with widespread effects on gene expression and signaling. As a result of these functions, one-carbon and polyamine metabolism have recently drawn a lot of interest for their part in cancer malignancy. Therapeutic inhibitors that target one-carbon and polyamine metabolism have thus been trialed as anticancer medications. The significance and future possibilities of one-carbon and polyamine metabolism as a target in cancer therapy are discussed in this review. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies II)

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48 pages, 2856 KiB

Open AccessReview

Druggable Metabolic Vulnerabilities Are Exposed and Masked during Progression to Castration Resistant Prostate Cancer

by Stephen Y. C. Choi, Caroline Fidalgo Ribeiro, Yuzhuo Wang, Massimo Loda, Stephen R. Plymate and Takuma Uo

Biomolecules 2022, 12(11), 1590; https://doi.org/10.3390/biom12111590 - 28 Oct 2022

Cited by 5 | Viewed by 3771

Abstract

There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to [...] Read more.

There is an urgent need for exploring new actionable targets other than androgen receptor to improve outcome from lethal castration-resistant prostate cancer. Tumor metabolism has reemerged as a hallmark of cancer that drives and supports oncogenesis. In this regard, it is important to understand the relationship between distinctive metabolic features, androgen receptor signaling, genetic drivers in prostate cancer, and the tumor microenvironment (symbiotic and competitive metabolic interactions) to identify metabolic vulnerabilities. We explore the links between metabolism and gene regulation, and thus the unique metabolic signatures that define the malignant phenotypes at given stages of prostate tumor progression. We also provide an overview of current metabolism-based pharmacological strategies to be developed or repurposed for metabolism-based therapeutics for castration-resistant prostate cancer. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies II)

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19 pages, 1491 KiB

Open AccessReview

Searching for the Metabolic Signature of Cancer: A Review from Warburg’s Time to Now

by Pierre Jacquet and Angélique Stéphanou

Biomolecules 2022, 12(10), 1412; https://doi.org/10.3390/biom12101412 - 02 Oct 2022

Cited by 7 | Viewed by 2410

Abstract

This review focuses on the evolving understanding that we have of tumor cell metabolism, particularly glycolytic and oxidative metabolism, and traces back its evolution through time. This understanding has developed since the pioneering work of Otto Warburg, but the understanding of tumor cell [...] Read more.

This review focuses on the evolving understanding that we have of tumor cell metabolism, particularly glycolytic and oxidative metabolism, and traces back its evolution through time. This understanding has developed since the pioneering work of Otto Warburg, but the understanding of tumor cell metabolism continues to be hampered by misinterpretation of his work. This has contributed to the use of the new concepts of metabolic switch and metabolic reprogramming， that are out of step with reality. The Warburg effect is often considered to be a hallmark of cancer, but is it really? More generally, is there a metabolic signature of cancer? We draw the conclusion that the signature of cancer cannot be reduced to a single factor, but is expressed at the tissue level in terms of the capacity of cells to dynamically explore a vast metabolic landscape in the context of significant environmental heterogeneities. Full article

(This article belongs to the Special Issue Targeting Tumor Metabolism: From Mechanisms to Therapies II)

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