Glioblastoma Stem-Like Cells, Metabolic Strategy to Kill a Challenging Target

Over the years, substantial evidence has definitively confirmed the existence of cancer stem-like cells within tumors such as Glioblastoma (GBM). The importance of Glioblastoma stem-like cells (GSCs) in tumor progression and relapse clearly highlights that cancer eradication requires killing of GSCs that are intrinsically resistant to conventional therapies as well as eradication of the non-GSCs cells since GSCs emergence relies on a dynamic process. The past decade of research highlights that metabolism is a significant player in tumor progression and actually might orchestrate it. The growing interest in cancer metabolism reprogrammation can lead to innovative approaches exploiting metabolic vulnerabilities of cancer cells. These approaches are challenging since they require overcoming the compensatory and adaptive responses of GSCs. In this review, we will summarize the current knowledge on GSCs with a particular focus on their metabolic complexity. We will also discuss potential approaches targeting GSCs metabolism to potentially improve clinical care

Deletion of UCP2 in iNOS Deficient Mice Reduces the Severity of the Disease during Experimental Autoimmune Encephalomyelitis

Uncoupling protein 2 is a member of the mitochondrial anion carrier family that is widely expressed in neurons and the immune cells of humans. Deletion of Ucp2 gene in mice pre-activates the immune system leading to higher resistance toward infection and to an increased susceptibility to develop chronic inflammatory diseases as previously exemplified with the Experimental Autoimmune Encephalomyelitis (EAE), a mouse model for multiple sclerosis. Given that oxidative stress is enhanced in Ucp2−/− mice and that nitric oxide (NO) also plays a critical function in redox balance and in chronic inflammation, we generated mice deficient for both Ucp2 and iNos genes and submitted them to EAE. Mice lacking iNos gene exhibited the highest clinical score (3.4+/−0.5 p<0.05). Surprisingly, mice deficient for both genes developed milder disease with reduced immune cell infiltration, cytokines and ROS production as compared to iNos−/− mice

UCP2 as a Cancer Target through Energy Metabolism and Oxidative Stress Control

Despite numerous therapies, cancer remains one of the leading causes of death worldwide due to the lack of markers for early detection and response to treatment in many patients. Technological advances in tumor screening and renewed interest in energy metabolism have allowed us to identify new cellular players in order to develop personalized treatments. Among the metabolic actors, the mitochondrial transporter uncoupling protein 2 (UCP2), whose expression is increased in many cancers, has been identified as an interesting target in tumor metabolic reprogramming. Over the past decade, a better understanding of its biochemical and physiological functions has established a role for UCP2 in (1) protecting cells from oxidative stress, (2) regulating tumor progression through changes in glycolytic, oxidative and calcium metabolism, and (3) increasing antitumor immunity in the tumor microenvironment to limit cancer development. With these pleiotropic roles, UCP2 can be considered as a potential tumor biomarker that may be interesting to target positively or negatively, depending on the type, metabolic status and stage of tumors, in combination with conventional chemotherapy or immunotherapy to control tumor development and increase response to treatment. This review provides an overview of the latest published science linking mitochondrial UCP2 activity to the tumor context

Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy

International audienceOver the past decade, advances in cancer immunotherapy through PD1–PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy

Le rôle anti-oxydant de la protéine découplante mitochondriale UCP2

LE KREMLIN-B.- PARIS 11-BU Méd (940432101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

UCP2 induces metabolic reprogramming to inhibit proliferation of cancer cells

International audienceInvalidation of uncoupling protein 2 (Ucp2) increases glucose utilization and proliferation in normal cells. Werecently reported that cancer cells that overexpress UCP2 become less tumorigenic while switching their metabolism from glycolysis to oxidative phosphorylation. UCP2 appears to be a key regulator of cellular metabolism with a relevant function against tumorigenesis

UCPs, at the interface between bioenergetics and metabolism

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UCP2 induces metabolic reprogramming to inhibit proliferation of cancer cells

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Mastermind-like 1 Is a specific coactivator of beta-catenin transcription activation and is essential for colon carcinoma cell survival

Misregulation of the Wnt signaling pathway has been linked to many human cancers including colon carcinoma and melanoma. The primary mediator of the oncogenic effects of the Wnt signaling pathway is beta-catenin. Accumulation of nuclear beta-catenin and transcription activation of lymphoid enhancer factor 1 (LEF1)/T-cell factor (TCF) target genes underlie the oncogenic activity. However, the mechanism of beta-catenin-mediated transcriptional activation remains poorly understood. In this study, we identified Mastermind-like 1 (Maml1), which is thought to be a specific coactivator for the Notch pathway, as a coactivator for beta-catenin. We found that Maml1 participates in the Wnt signaling by modulating the beta-catenin/TCF activity. We show in vivo that Maml1 is recruited by beta-catenin on the cyclin D1 and c-Myc promoters. Importantly, we show that Maml1 functions in the Wnt/beta-catenin pathway independently of Notch signaling. Finally, we show that the knockdown of Mastermind-like family proteins in colonic carcinoma cells results in cell death by affecting beta-catenin-induced expression of cyclin D1 and c-Myc. This is the first demonstration of a role for the Mastermind-like family in another signaling pathway and that the knockdown of Mastermind-like family function leads to tumor cell death

Mastermind-like 1 Is a specific coactivator of beta-catenin transcription activation and is essential for colon carcinoma cell survival.

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