GLUT1 inhibition blocks growth of RB1-positive Triple Negative Breast Cancer

Wu, Qin; Ba-Alawi, Wail; Deblois, Geneviève; Cruickshank, Jennifer; Duan, Shili; Lima‐Fernandes, Evelyne; Haight, Jillian; Tonekaboni, Seyed Ali Madani; Fortier, Anne-Marie; Kuasne, Hellen; McKee, Trevor D.; Mahmoud, Hassan; Cameron, Sarina; Dogan-Artun, Nergiz; Chen, Wenjun; Vellanki, Ravi N.; Zhou, Stanley; Done, Susan J.; Park, Morag; Cescon, David W.; Haibe‐Kains, Benjamin; Lupien, Mathieu; Arrowsmith, C.H.

doi:10.1101/764944

Cited by 8 publications

(8 citation statements)

References 83 publications

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“…As heptelidic acid should act only on tumor cells and immune cells, in particular activated neutrophils 20 , this divergent phenotype indicates that the effect of GAPDH down-modulation on immune cells in the host outweighs its inhibitory effect on tumor growth. Targeting of upstream molecules, like GLUT1, show similar effects in inhibiting tumor growth but may cause normal cell death because they prevent oxygen transport and endothelial cell angiogenesis for red blood cells 48,49 . These findings provide a powerful proof-of-concept that paradoxical tumor-host responses to treatment occur in vivo, warranting further investigation in the context of other treatments 50 .…”

Section: Discussionmentioning

confidence: 99%

Early neutrophilia marked by aerobic glycolysis sustains host metabolism and delays cancer cachexia

Petruzzelli

Ferrer

Schuijs

et al. 2021

Preprint

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An elevated neutrophil-to-lymphocyte ratio negatively predicts the outcome of patients with cancer and is associated with cachexia, the terminal wasting syndrome. Here, we show using murine model systems of colorectal and pancreatic cancer that neutrophilia in the circulation and multiple organs, accompanied by extramedullary hematopoiesis, is an early event during cancer progression. Transcriptomic and metabolic assessment reveals that neutrophils in tumor-bearing animals utilize aerobic glycolysis, alike to cancer cells. Although pharmacological inhibition of aerobic glycolysis slows down tumor growth in C26 tumor-bearing mice, it precipitates cachexia, thereby shortening overall survival. This negative effect may be explained by our observation that acute depletion of neutrophils in pre-cachectic mice impairs systemic glucose homeostasis secondary to altered hepatic lipid processing. Thus, changes in neutrophil number, distribution and metabolism play an adaptive role in host metabolic homeostasis during cancer progression. Our findings provide insight into early events during cancer progression to cachexia, with implications for therapy.

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Section: Discussionmentioning

confidence: 99%

Early neutrophilia marked by aerobic glycolysis sustains host metabolism and delays cancer cachexia

Petruzzelli

Ferrer

Schuijs

et al. 2021

Preprint

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“…To determine if the loss of GLUT1 function directly impairs NP cell metabolism, we modeled the loss of GLUT1 in NP cells in vitro with two highly specific pharmacological inhibitors; namely, BAY-876 and WZB-117 (35,36). Using a Seahorse Flux Analyzer, we assessed metrics of NP cell glycolytic flux by measuring Extracellular Acidification Rate (ECAR) and oxidative flux by oxygen consumption rate (OCR).…”

Section: Long-term Inhibition Of Glut1 Does Not Affect Glycolytic or ...mentioning

confidence: 99%

GLUT1 is redundant in hypoxic and glycolytic nucleus pulposus cells of the intervertebral disc

Johnston¹,

Silagi²,

Madhu³

et al. 2023

JCI Insight

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Glycolysis is central to homeostasis of nucleus pulposus (NP) cells in the avascular intervertebral disc. Since the glucose importer, GLUT1, is a highly enriched phenotypic marker of NP cells, we hypothesized that it is vital for the development and post-natal maintenance of the disc. Surprisingly, primary NP cells treated with two well-characterized GLUT1 inhibitors maintained normal rates of glycolysis and ATP production, indicating intrinsic compensatory mechanisms.We show in vitro that NP cells mitigate GLUT1 loss by rewiring glucose import through GLUT3.Noteworthy, we demonstrate that substrates, such as glutamine and palmitate, do not compensate for glucose restriction resulting from dual inhibition of GLUT1/3 and inhibition compromises long-term cell viability. To investigate the redundancy of GLUT1 function in NP, we generated two NP-specific knockout mice: Krt19 CreERT ; Glut1 f/f and Foxa2 Cre ; Glut1 f/f . Noteworthy, there were no apparent defects in post-natal disc health or development and maturation in mutant mice. Microarray analysis confirmed that GLUT1 loss did not cause transcriptomic alterations in the NP, supporting that cells are refractory to GLUT1 loss. These observations provide the first evidence of functional redundancy in GLUT transporters in the physiologically hypoxic intervertebral disc and underscore the importance of glucose as the indispensable substrate for NP cells.

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“…GLUT1 was also evidenced to be influenced by intracellular signalling pathways including protein kinase C (PKC) (Lee et al, 2015). Genetic silencing or pharmacological inhibition of GLUT1 reduced the growth of a subset of triple negative breast cancer (TNBC) tumours which were expressing retinoblastoma tumour suppressor RB1 and were displaying increased glycolytic rates (Wu et al, 2020). Moreover, the phosphatidyl-inositol 3-kinase (PI3K) -Akt signalling axis has been shown to increase GLUT1 expression and trafficking to the cell membrane in an interleukin-3 dependent manner (Wieman et al, 2007).…”

Section: Glucose Transportmentioning

confidence: 99%