PKCs Sweeten Cell Metabolism by Phosphorylation of Glut1

Siska, Peter J.; Rathmell, Jeffrey C.

doi:10.1016/j.molcel.2015.05.025

Cited by 15 publications

(9 citation statements)

References 10 publications

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“…Moreover, GLUT1 silencing suppressed PKC-iota-mediated 18 F-FDG accumulation and subsequent glycolysis in NSCLC cells. Taken together, we confirmed that PKC-iota regulated glycolysis via c-Myc/GLUT1 signaling; the regulatory effect of PKC-iota on GLUT1 occurred at the transcriptional level; the most likely reason for the decrease in active, membrane-located GLUT1 induced by PKC-iota knockdown, which was also observed in our research, is the overall decrease in GLUT1 induced by c-Myc downregulation, which might differ from direct phosphorylation and activation of GLUT1 by other PKCs at the post-translational level 14…”

Section: Discussionsupporting

confidence: 75%

“…PKC-iota is the first PKC reported as an oncogenic enzyme in NSCLC,10 and contributes to tumor progression via immune suppression, cell cycle deregulation, and pericellular degradation of the extracellular matrix 11–13. Although other PKCs were reported to directly phosphorylate glucose transporter 1 (GLUT1), which is the key rate-limiting carrier in charge of glucose transportation, thereby promoting its activation and the transport of glucose across plasma membranes,14 the regulatory effect of PKC-iota on GLUT1 is not yet well established. Whether PKC-iota is involved in glucose metabolism in tumors remains unknown.…”

Section: Introductionmentioning

confidence: 99%

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<p>Protein kinase C-iota-mediated glycolysis promotes non-small-cell lung cancer progression</p>

Liu

Wang

et al. 2019

OTT

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Purpose To determine whether protein kinase C-iota (PKC-iota) is associated with glucose metabolism in non-small-cell lung cancer (NSCLC) and whether its regulatory effect on metabolic and biological changes observed in NSCLC can be mediated by glucose transporter 1 (GLUT1). Patients and methods Forty-five NSCLC patients underwent combined 18 F-fludeoxyglucose ( 18 F-FDG) positron emission tomography and computed tomography (PET/CT) before surgery, and another eighty-one NSCLC patients were followed-up for 1–91 months after tumor resection. The rate of glucose metabolism in NSCLC was quantified by measuring the maximum standardized uptake value (SUVmax) by 18 F-FDG PET/CT. PKC-iota and GLUT1 in NSCLC were detected by immunostaining. In vitro, PKC-iota was knocked down, whereas GLUT1 was silenced with or without PKC-iota overexpression to identify the role of PKC-iota in glycolysis. Spearman’s rank correlation coefficient was used in the correlation analysis. Kaplan-Meier analysis was used to assess survival duration. Results There was a positive relationship between PKC-iota expression and SUVmax in NSCLC (r=0.649, P <0.001). PKC-iota expression also showed a positive relationship with GLUT1 in NSCLC tissues (r=0.686, P <0.001). Patients whose NSCLC tissues highly co-expressed PKC-iota and GLUT1 had worse prognosis compared with patients without high co-expression of PKC-iota and GLUT1. In vitro, PKC-iota silencing significantly decreased the expression of GLUT1 and inhibited glucose uptake and glycolysis; c-Myc silencing restrained PKC-iota-mediated GLUT1 elevation; GLUT1 knockdown remarkably suppressed PKC-iota-mediated glycolysis and cell growth. Conclusion In NSCLC, the rate of glucose metabolism was positively correlated with PKC-iota expression. PKC-iota increased glucose accumulation and glycolysis by upregulating c-Myc/GLUT1 signaling and is thus involved in tumor progression.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

<p>Protein kinase C-iota-mediated glycolysis promotes non-small-cell lung cancer progression</p>

Liu

Wang

et al. 2019

OTT

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“…Cancer cells consume nutrients and in particular, glucose to sustain their proliferation, restricting glucose availability to TILs (67). Glucose deprivation impedes CD8 + TIL effector function by limiting aerobic glycolysis, decreasing mTOR activity and IFN-γ production.…”

Section: Metabolic Checkpointsmentioning

confidence: 99%

Reversing T-cell Dysfunction and Exhaustion in Cancer

Zarour

2016

Clinical Cancer Research

348

299

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In the context of chronic antigen exposure in chronic viral infections and cancer, T cells become exhausted/dysfunctional. These exhausted T cells exhibit defective proliferative capacities and cytokine production, but are not totally inert and may exert lytic functions. Importantly, exhausted T cells upregulate multiple inhibitory receptors (IRs)/immune checkpoints that bind to their ligands expressed by tumor cells and antigen-presenting cells (APCs) in the tumor microenvironment (TME). Immune checkpoint blockades with anti-cytotoxic T lymphocyte antigen 4 (CTLA-4) and/or anti- programmed death 1 (PD-1) monoclonal antibodies (mAbs) successfully reinvigorate tumor-infiltrating T lymphocytes (TILs) and provide persistent clinical benefits to a large number of patients with advanced cancer. This great and long-awaited success for the immunotherapy of cancer has infused considerable enthusiasm in the field of oncology and fostered the development of combinatorial strategies to target the multiple mechanisms of tumor-induced T cell dysfunction. Here, we propose to review the critical immunoregulatory mechanisms driving T cell exhaustion in the TME. We will also discuss the development of promising combinatorial immunotherapies to counteract the mechanisms of tumor-induced T cell dysfunction to improve the clinical efficacy of current immune checkpoint blockades. As our understanding of the mechanisms supporting tumor-induced T cell dysfunction improves based upon preclinical and clinical studies, we expect that novel combinatorial immunotherapies will emerge to improve the clinical outcome of patients with advanced cancers.

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“…GLUT1 was also suggested to be the receptor for human T‐lymphotropic virus (HTLV) and play an essential role in CD4 T cell activation . The transport activity of GLUT1 is subjected to regulation by PKC and TXNIP . Several dozens of SLC2A1 mutations have been identified in patients with the autosomal dominant genetic disease known as GLUT1 deficiency syndrome …”

Section: Physiological Functions Of Glucose Transportersmentioning

confidence: 99%

GLUT, SGLT, and SWEET: Structural and mechanistic investigations of the glucose transporters

2016

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Glucose is the primary fuel to life on earth. Cellular uptake of glucose is a fundamental process for metabolism, growth, and homeostasis. Three families of secondary glucose transporters have been identified in human, including the major facilitator superfamily glucose facilitators GLUTs, the sodium-driven glucose symporters SGLTs, and the recently identified SWEETs. Structures of representative members or their prokaryotic homologs of all three families were obtained. This review focuses on the recent advances in the structural elucidation of the glucose transporters and the mechanistic insights derived from these structures, including the molecular basis for substrate recognition, alternating access, and stoichiometric coupling of co-transport.

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PKCs Sweeten Cell Metabolism by Phosphorylation of Glut1

Abstract: In this issue, Lee et al. (2015) show that PKC directly phosphorylates the glucose transporter Glut1, in order to promote glucose uptake in response to growth factor signaling.

Cited by 15 publications

References 10 publications

<p>Protein kinase C-iota-mediated glycolysis promotes non-small-cell lung cancer progression</p>

<p>Protein kinase C-iota-mediated glycolysis promotes non-small-cell lung cancer progression</p>

Reversing T-cell Dysfunction and Exhaustion in Cancer

GLUT, SGLT, and SWEET: Structural and mechanistic investigations of the glucose transporters

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