Involvement of Lipid Metabolism in the Tumoral Progression and Tumor Resistance

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (20 September 2020) | Viewed by 17212

Special Issue Editor


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Guest Editor
1. Inserm Research Center UMR1231 "Lipids, Nutrition, Cancer", Université de Bourgogne, 7 Blvd Jeanne d’Arc, 21000 Dijon, France
2. Centre de Lutte Contre le Cancer Georges-François Leclerc Center, 21000 Dijon, France
Interests: polyhenols; flavonoids; degenerative age-related diseases; inflammation; cancers; chemosensitization; lipid metabolism
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Special Issue Information

Dear Colleagues,

Metabolic reprogramming is a common feature of cancer progression and metastasis. Tumors main metabolic adaptation regardless oxygen abundance is an acute glucose uptake and aerobic glycolysis at the expense of mitochondrial respiration as part of the Warburg effect. Besides this glycolytic switch, tumor cells also undergo lipid remodeling mostly characterized by aberrant de novo lipogenesis, cholesterogenesis due to oncogenic-driven lipogenic enzymes overexpression (e.g., fatty-acid synthase (FASN), stearoyl-CoA desaturase (SCD), 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)) that can further be potentiated under hypoxic tumor conditions through the activation of hypoxia-inducible factor 1-alpha. This bulk of newly synthesized lipids serves for membrane biogenesis and synthesis of essential lipid-derived second messengers (e.g., phosphatidic acid, phosphoinositides, eicosanoids including prostaglandin E2) to maintain cancer cell proliferation and survival.

Recent studies have also shown that complex lipids such as phospholipids or particular organelles such as lipid droplets could also contribute to the emergence of drug resistance. These same lipids and the resulting biosynthetic pathways have been suggested as potential biomarkers for tumor progression and treatment response.

Nevertheless, the relationships between alteration of cellular lipid metabolism, tumor progression and resistance to chemotherapeutic treatments need to be better clarified. This special issue will highlight the current state of the relation between lipid metabolism and cancer progression to advance our understanding of tumor to treatment response and future prospects for improving therapies through a modulation of tumor lipid metabolism.

Prof. Dr. Dominique Delmas
Guest Editor

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Keywords

  • Lipid Metabolism
  • Lipid Droplets
  • Complex Lipids
  • Drug Resistance
  • Cancer Progression
  • Lipogenesis
  • Treatment Response

Published Papers (4 papers)

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Research

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14 pages, 1789 KiB  
Article
Dendrogenin A Enhances Anti-Leukemic Effect of Anthracycline in Acute Myeloid Leukemia
by Pierre-Luc Mouchel, Nizar Serhan, Rémy Betous, Thomas Farge, Estelle Saland, Philippe De Medina, Jean-Sébastien Hoffmann, Jean-Emmanuel Sarry, Marc Poirot, Sandrine Silvente-Poirot and Christian Récher
Cancers 2020, 12(10), 2933; https://doi.org/10.3390/cancers12102933 - 12 Oct 2020
Cited by 7 | Viewed by 2911
Abstract
Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML [...] Read more.
Dendrogenin A (DDA), a mammalian cholesterol metabolite with tumor suppressor properties, has recently been shown to exhibit strong anti-leukemic activity in acute myeloid leukemia (AML) cells by triggering lethal autophagy. Here, we demonstrated that DDA synergistically enhanced the toxicity of anthracyclines in AML cells but not in normal hematopoietic cells. Combination index of DDA treatment with either daunorubicin or idarubicin indicated a strong synergism in KG1a, KG1 and MV4-11 cell lines. This was confirmed in vivo using immunodeficient mice engrafted with MOLM-14 cells as well as in a panel of 20 genetically diverse AML patient samples. This effect was dependent on Liver X Receptor β, a major target of DDA. Furthermore, DDA plus idarubicin strongly increased p53BP1 expression and the number of DNA strand breaks in alkaline comet assays as compared to idarubicin alone, whereas DDA alone was non-genotoxic. Mechanistically, DDA induced JNK phosphorylation and the inhibition of AKT phosphorylation, thereby maximizing DNA damage induced by idarubicin and decreasing DNA repair. This activated autophagic cell death machinery in AML cells. Overall, this study shows that the combination of DDA and idarubicin is highly promising and supports clinical trials of dendrogenin A in AML patients. Full article
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16 pages, 3799 KiB  
Article
Loss of HMGCS2 Enhances Lipogenesis and Attenuates the Protective Effect of the Ketogenic Diet in Liver Cancer
by Yuan-Hsi Wang, Fat-Moon Suk and Yi-Jen Liao
Cancers 2020, 12(7), 1797; https://doi.org/10.3390/cancers12071797 - 4 Jul 2020
Cited by 20 | Viewed by 5426
Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor with limited treatment. The ketogenic diet (KD) emerged as a metabolic therapy for cancer; however, the antitumor effect on HCC remains controversial. We previously reported that the ketogenesis rate-limiting enzyme, 3-hydroxymethylglutaryl-CoA synthase [...] Read more.
Hepatocellular carcinoma (HCC) is the most common primary malignant liver tumor with limited treatment. The ketogenic diet (KD) emerged as a metabolic therapy for cancer; however, the antitumor effect on HCC remains controversial. We previously reported that the ketogenesis rate-limiting enzyme, 3-hydroxymethylglutaryl-CoA synthase 2 (HMGCS2), was downregulated in most patients with HCC. The knockdown of HMGCS2 enhanced the proliferation and metastasis ability of HCC cells. However, the role of HMGCS2 in affecting KD-mediated metabolic effects remains unclear. Here, we report that KD feeding upregulates HMGCS2 expression and inhibits HCC tumor growth, while a reverse correlation between tumor size and HMGCS2 expression was observed. We found that HCC cells with HMGCS2 downregulation possess altered lipid metabolism that increases fatty acid, triglyceride, and cholesterol synthesis. Under KD feeding, a higher tumor growth rate was observed in HMGCS2 knockdown tumors, which had increased lipid synthesis-related marker expression and a positive correlation between lipid quantity and tumor weight. In conclusion, these results demonstrate that the downregulation of HMGCS2 attenuates the protective effect of the KD by shifting ketone production to enhance de novo lipogenesis in HCC. Our study elucidates a new molecular mechanism underlying the crosstalk between HMGCS2 expression and the KD in cancer treatment, which provides more information for precision medicine in developing personalized treatment strategies. Full article
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Review

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17 pages, 2842 KiB  
Review
Emergence of Lipid Droplets in the Mechanisms of Carcinogenesis and Therapeutic Responses
by Dominique Delmas, Alexia K. Cotte, Jean-Louis Connat, François Hermetet, Florence Bouyer and Virginie Aires
Cancers 2023, 15(16), 4100; https://doi.org/10.3390/cancers15164100 - 14 Aug 2023
Cited by 3 | Viewed by 1401
Abstract
Cancer shares common risk factors with cardiovascular diseases such as dyslipidemia, obesity and inflammation. In both cases, dysregulations of lipid metabolism occur, and lipid vesicles emerge as important factors that can influence carcinogenesis. In this review, the role of different lipids known to [...] Read more.
Cancer shares common risk factors with cardiovascular diseases such as dyslipidemia, obesity and inflammation. In both cases, dysregulations of lipid metabolism occur, and lipid vesicles emerge as important factors that can influence carcinogenesis. In this review, the role of different lipids known to be involved in cancer and its response to treatments is detailed. In particular, lipid droplets (LDs), initially described for their role in lipid storage, exert multiple functions, from the physiological prevention of LD coalescence and regulation of endoplasmic reticulum homeostasis to pathological involvement in tumor progression and aggressiveness. Analysis of LDs highlights the importance of phosphatidylcholine metabolism and the diversity of lipid synthesis enzymes. In many cancers, the phosphatidylcholine pathways are disrupted, modifying the expression of genes coding for metabolic enzymes. Tumor microenvironment conditions, such as hypoxia, different types of stress or inflammatory conditions, are also important determinants of LD behavior in cancer cells. Therefore, LDs represent therapeutic targets in cancer, and many lipid mediators have emerged as potential biomarkers for cancer onset, progression, and/or resistance. Full article
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21 pages, 1350 KiB  
Review
Lipid Metabolism in Development and Progression of Hepatocellular Carcinoma
by Moris Sangineto, Rosanna Villani, Francesco Cavallone, Antonino Romano, Domenico Loizzi and Gaetano Serviddio
Cancers 2020, 12(6), 1419; https://doi.org/10.3390/cancers12061419 - 31 May 2020
Cited by 88 | Viewed by 6933
Abstract
Metabolic reprogramming is critically involved in the development and progression of cancer. In particular, lipid metabolism has been investigated as a source of energy, micro-environmental adaptation, and cell signalling in neoplastic cells. However, the specific role of lipid metabolism dysregulation in hepatocellular carcinoma [...] Read more.
Metabolic reprogramming is critically involved in the development and progression of cancer. In particular, lipid metabolism has been investigated as a source of energy, micro-environmental adaptation, and cell signalling in neoplastic cells. However, the specific role of lipid metabolism dysregulation in hepatocellular carcinoma (HCC) has not been widely described yet. Alterations in fatty acid synthesis, β-oxidation, and cellular lipidic composition contribute to initiation and progression of HCC. The aim of this review is to elucidate the mechanisms by which lipid metabolism is involved in hepatocarcinogenesis and tumour adaptation to different conditions, focusing on the transcriptional aberrations with new insights in lipidomics and lipid zonation. This will help detect new putative therapeutic approaches in the second most frequent cause of cancer-related death. Full article
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