bims-glucam 2022-06-19 papers

Cell Mol Gastroenterol Hepatol. 2022 Jun 14. pii: S2352-345X(22)00102-3. [Epub ahead of print]

Deletion of Lactate Dehydrogenase-A Impairs Oncogene-Induced Mouse Hepatocellular Carcinoma Development.

Marina Serra, Mario Di Matteo, Jens Serneels, Rajesh Pal, Sarah Trusso Cafarello, Martina Lanza, Carlos Sanchez-Martin, Matthias Evert, Alessandra Castegna, Diego Francesco Calvisi, Massimiliano Mazzone, Amedeo Columbano.

BACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a multistep process whereby abnormally proliferating cancer cells undergo extensive metabolic reprogramming. Metabolic alterations in hepatocarcinogenesis depend on the activation of specific oncogenes, thus partially explaining HCC heterogeneity. C-Myc oncogene overexpression, frequently observed in human HCCs, leads to a metabolic rewiring toward a Warburg phenotype and production of lactate, resulting in the acidification of the extracellular space, favoring the emergence of an immune-permissive tumor microenvironment. Here, we investigated whether Lactate dehydrogenase alpha (Ldha) genetic ablation interferes with metabolic reprogramming and HCC development in the mouse.
METHODS: We characterized the metabolic reprogramming in tumors induced in C57BL/6J mice hydrodynamically co-transfected with c-Myc and h-Ras. Using the same experimental model, we investigated the effect of Ldha inhibition - gained through the inducible and hepatocyte-specific Ldha knockout - on cancer cell metabolic reprogramming, number and size of HCC lesions, and TME alterations.
RESULTS: C-Myc/h-Ras driven tumors display a striking glycolytic metabolism, suggesting a switch to a Warburg phenotype. The tumors also exhibited enhanced pentose phosphate pathway activity, the switch of glutamine to sustain glutathione synthesis instead of Tricarboxylic acid cycle, and the impairment of oxidative phosphorylation. In addition, Ldha abrogation significantly hampered tumor number and size together with an evident inhibition of the Warburg-like metabolic feature and a remarkable increase of CD4+ lymphocytes compared to Ldha wild-type livers.
CONCLUSIONS: These results demonstrate that Ldha deletion significantly impairs mouse HCC development and suggest LDH as a potential target to enhance the efficacy of the current therapeutic options.

Keywords: C-Myc; HCC; Ldha; Metabolic Reprogramming; TME

DOI: https://doi.org/10.1016/j.jcmgh.2022.06.003

Biochem J. 2022 Jun 17. 479(11): 1221-1235

Endogenous glutamine is rate-limiting for anti-CD3 and anti-CD28 induced CD4+ T-cell proliferation and glycolytic activity under hypoxia and normoxia.

Jonas A Wik, Azazul Chowdhury, Shrikant Kolan, Nasser E Bastani, Gaoyang Li, Kazi Alam, Franco Grimolizzi, Bjørn S Skålhegg.

To meet the demand for energy and biomass, T lymphocytes (T cells) activated to proliferation and clonal expansion, require uptake and metabolism of glucose (Gluc) and the amino acid (AA) glutamine (Gln). Whereas exogenous Gln is converted to glutamate (Glu) by glutaminase (GLS), Gln is also synthesized from the endogenous pool of AA through Glu and activity of glutamine synthase (GS). Most of this knowledge comes from studies on cell cultures under ambient oxygen conditions (normoxia, 21% O2). However, in vivo, antigen induced T-cell activation often occurs under moderately hypoxic (1-4% O2) conditions and at various levels of exogenous nutrients. Here, CD4+ T cells were stimulated for 72 h with antibodies targeting the CD3 and CD28 markers at normoxia and hypoxia (1% O2). This was done in the presence and absence of the GLS and GS inhibitors, Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and methionine sulfoximine (MSO) and at various combinations of exogenous Gluc, Gln and pyruvate (Pyr) for the last 12 h of stimulation. We found that T-cell proliferation, viability and levels of endogenous AA were significantly influenced by the availability of exogenous Gln, Gluc and Pyr as well as inhibition of GLS and GS. Moreover, inhibition of GLS and GS and levels of oxygen differentially influenced oxygen consumption rate (OCR) and extracellular acidification rate (ECAR). Finally, BPTES-dependent down-regulation of ECAR was associated with reduced hexokinase (HK) activity at both normoxia and hypoxia. Our results demonstrate that Gln availability and metabolism is rate-limiting for CD4+ T-cell activity.

Keywords: BPTES; CD4+ T cells; glutamine; hypoxia; metabolism; normoxia

DOI: https://doi.org/10.1042/BCJ20220144

Am J Cancer Res. 2022 ;12(5): 2249-2276

Targeting the methionine addiction of cancer.

Joni C Sedillo, Vincent L Cryns.

Methionine is the initiator amino acid for protein synthesis, the methyl source for most nucleotide, chromatin, and protein methylation, and the carbon backbone for various aspects of the cellular antioxidant response and nucleotide biosynthesis. Methionine is provided in the diet and serum methionine levels fluctuate based on dietary methionine content. Within the cell, methionine is recycled from homocysteine via the methionine cycle, which is linked to nutrient status via one-carbon metabolism. Unlike normal cells, many cancer cells, both in vitro and in vivo, show high methionine cycle activity and are dependent on exogenous methionine for continued growth. However, the molecular mechanisms underlying the methionine dependence of diverse malignancies are poorly understood. Methionine deprivation initiates widespread metabolic alterations in cancer cells that enable them to survive despite limited methionine availability, and these adaptive alterations can be specifically targeted to enhance the activity of methionine deprivation, a strategy we have termed "metabolic priming". Chemotherapy-resistant cell populations such as cancer stem cells, which drive treatment-resistance, are also sensitive to methionine deprivation, suggesting dietary methionine restriction may inhibit metastasis and recurrence. Several clinical trials in cancer are investigating methionine restriction in combination with other agents. This review will explore new insights into the mechanisms of methionine dependence in cancer and therapeutic efforts to translate these insights into enhanced clinical activity of methionine restriction in cancer.

Keywords: Methionine; cancer therapy; epigenetics; metabolism; nutrition; one-carbon; oxidative stress

Br J Cancer. 2022 Jun 17.

Recent insights into the effects of metabolism on breast cancer cell dormancy.

Sara Bartlome, Catherine Cecilia Berry.

Breast cancer (BC) remains the most common cancer, as well as the leading cause of cancer mortality in women worldwide [1]. Approximately 30% of patients with early-stage BC experience metastasis or a recurrent form of the disease [2]. The phenomenon of BC dormancy, where metastasised cancer cells remain in a quiescent phase at their disseminated location and for unknown reasons can become actively proliferative again, further adds to BC's clinical burden with treatment at this secondary stage typically proving futile. An emerging avenue of research focuses on the metabolic properties of dormant BC cells (BCCs) and potential metabolic changes causing BCCs to enter/exit their quiescent state. Here we explore several studies that have uncovered changes in carbon metabolism underlying a dormant state, with conflicting studies uncovering shifts towards both glycolysis and/or oxidative phosphorylation. This review highlights that the metabolic states/shifts of dormant BCCs seem to be dependent on different BC subtypes and receptor status; however, more work needs to be done to fully map these differences. Building on the research that this review outlines could provide new personalised therapeutic possibilities for BC patients.

DOI: https://doi.org/10.1038/s41416-022-01869-5