Phosphoglucose Isomerase/Autocrine Motility Factor Mediates Epithelial and Mesenchymal Phenotype Conversions in Breast Cancer

Funasaka, Tatsuyoshi; Hogan, Victor; Raz, Avraham

doi:10.1158/0008-5472.can-09-0488

Cited by 74 publications

(69 citation statements)

References 40 publications

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“…These moonlighting functions are not uncommon for enzymes in cancer. For example, aldolase A, 12 pyruvate kinase PKM isoform M2, 105 and glucose-6-phosphate isomerase (also called autocrine motility factor) 106 all have roles in cancer in addition to their enzymatic functions. Studies are currently underway in our laboratory to determine the underlying mechanism of this moonlighting function of AGL and how it relates to bladder cancer.…”

Section: Glycogen Metabolism In Bladder Cancermentioning

confidence: 99%

Targeting glycogen metabolism in bladder cancer

2015

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Metabolism has been a heavily investigated topic in cancer research for the past decade. Although the role of aerobic glycolysis (the Warburg effect) in cancer has been extensively studied, abnormalities in other metabolic pathways are only just being understood in cancer. One such pathway is glycogen metabolism; its involvement in cancer development, particularly in urothelial malignancies, and possible ways of exploiting aberrations in this process for treatment are currently being studied. New research shows that the glycogen debranching enzyme amylo-α-1,6-glucosidase, 4-α-glucanotransferase (AGL) is a novel tumour suppressor in bladder cancer. Loss of AGL leads to rapid proliferation of bladder cancer cells. Another enzyme involved in glycogen debranching, glycogen phosphorylase, has been shown to be a tumour promoter in cancer, including in prostate cancer. Studies demonstrate that bladder cancer cells in which AGL expression is lost are more metabolically active than cells with intact AGL expression, and these cells are more sensitive to inhibition of both glycolysis and glycine synthesis—two targetable pathways. As a tumour promoter and enzyme, glycogen phosphorylase can be directly targeted, and preclinical inhibitor studies are promising. However, few of these glycogen phosphorylase inhibitors have been tested for cancer treatment in the clinical setting. Several possible limitations to the targeting of AGL and glycogen phosphorylase might also exist.

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Section: Glycogen Metabolism In Bladder Cancermentioning

confidence: 99%

Targeting glycogen metabolism in bladder cancer

2015

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“…Similarly, autocrine motility factor (AMF), which is identical to glucose-6-phosphate isomerase (GPI), is an essential glycolytic enzyme that is secreted and increases the motility and metastatic capacity of cancer cells. 17 Perhaps extracellular PKM2 and LDH may serve a similar function. Alternatively, the secretion of glycolytic enzymes by cancer associated fibroblasts could allow glycolysis Figure 8.…”

Section: (Continued)mentioning

confidence: 99%

The reverse Warburg Effect: Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts

Bonuccelli¹,

et al. 2010

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“…Met receptor endocytosis has recently been linked to oncogenicity and Rac1 activation (Joffre et al, 2011). AMF stimulates cell motility and metastasis (Funasaka et al, 2009;Tsutsumi et al, 2003) and both AMF (A) Untransfected Cos7 cells or Cos7 cells transfected with Gp78 were treated with 100 mM of dynasore, the PI3K inhibitor LY294002 or the Rac1-inhibitor NSC23766 in the presence of 25 mg/ml AMF for 2 hours. Lysates were analyzed by western blotting for MFN1, MFN2 and b-actin expression, or immunoprecipitated with anti-Flag M2 agarose beads (300 mg protein) and immunoprecipitates blotted with anti-Flag mAb.…”

Section: Amf Inhibits Gp78-dependent Mitofusin Degradation and Mitochmentioning

confidence: 99%

Raft endocytosis of autocrine motility factor regulates mitochondrial dynamics via rac1 signaling and the gp78 ubiquitin ligase

Shankar

Kojic

St-Pierre

et al. 2013

Journal of Cell Science

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SummaryGp78 is a cell surface receptor that also functions as an E3 ubiquitin ligase in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. The Gp78 ligand, the glycolytic enzyme phosphoglucose isomerase (PGI; also called autocrine motility factor, AMF), functions as a cytokine upon secretion by tumor cells. AMF is internalized through a PI3K-and dynamin-dependent raft endocytic pathway to the smooth ER; however, the relationship between AMF and Gp78 ubiquitin ligase activity remains unclear. AMF uptake to the smooth ER is inhibited by the dynamin inhibitor, dynasore, is reduced in Gp78 knockdown cells and induces the dynamin-dependent downregulation of its cell surface receptor. AMF uptake is Rac1-dependent and is inhibited by expression of dominant-negative Rac1 and the Rac1 inhibitor NSC23766, and is therefore distinct from Cdc42-and RhoA-dependent raft endocytic pathways. AMF stimulates Rac1 activation, but this is reduced by dynasore treatment and is absent in Gp78-knockdown cells; therefore, AMF activities require Gp78-mediated endocytosis. AMF also prevents Gp78-induced degradation of the mitochondrial fusion proteins, mitofusin 1 and 2 in a dynamin-, Rac1-and phosphoinositide 3-kinase (PI3K)-dependent manner. Gp78 induces mitochondrial clustering and fission in a manner dependent on GP78 ubiquitin ligase activity, and this is also reversed by uptake of AMF. The raft-dependent endocytosis of AMF, therefore, promotes Rac1-PI3K signaling that feeds back to promote AMF endocytosis and also inhibits the ability of Gp78 to target the mitofusins for degradation, thereby preventing Gp78-dependent mitochondrial fission. Through regulation of an ER-localized ubiquitin ligase, the raft-dependent endocytosis of AMF represents an extracellular regulator of mitochondrial fusion and dynamics.

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Phosphoglucose Isomerase/Autocrine Motility Factor Mediates Epithelial and Mesenchymal Phenotype Conversions in Breast Cancer

Cited by 74 publications

References 40 publications

Targeting glycogen metabolism in bladder cancer

Targeting glycogen metabolism in bladder cancer

The reverse Warburg Effect: Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts

Raft endocytosis of autocrine motility factor regulates mitochondrial dynamics via rac1 signaling and the gp78 ubiquitin ligase

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