Antigen Presentation by Dendritic Cells in Tumors Is Disrupted by Altered Metabolism that Involves Pyruvate Kinase M2 and Its Interaction with SOCS3

Zhang, Zhuohan; Liu, Qiaofei; Che, Yongzhe; Yuan, Xin; Dai, Lingyun; Zeng, Bin; Jiao, Guohui; Yin, Zhifu; Wu, Xue; Yu, Yinyan; Zhang, Yuan; Yang, Rongcun

doi:10.1158/0008-5472.can-09-2970

Cited by 45 publications

(38 citation statements)

References 35 publications

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“…Various factors have been reported to control the switch between the dimeric and tetrameric forms of PKM2 (5,6,8,19,(36)(37)(38)(39)(40)(41)(42)(43)(44). For example, fructose-1,6-bisphosphate (fructose-1,6-P 2 ), a glycolytic intermediate, binds allosterically to PKM2 and facilitates the formation of the active tetramer.…”

Section: Glycolytic Functions Of Pkm2mentioning

confidence: 99%

“…A variety of molecules interact with PKM2 (5,6,8,14,18,19,21,23,24,28,(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62)(63)(64)(65). Many of them affect the glycolytic functions of PKM2, which directly regulate the Warburg effect.…”

Section: Nonglycolytic Functions Of Pkm2mentioning

confidence: 99%

“…The second is that the dimeric PKM2 translocated in the nucleus acts as an active protein kinase to phosphorylate specific nuclear proteins. Recently, many other roles of PKM2 in various conditions such as immunologic responses (43,44,63,64), genomic instability (37), angiogenesis (57), pathogenesis (36,41,62), and some disease (54) have been reported. It is important to define whether those events are associated with glycolytic or nonglycolytic functions of PKM2.…”

Section: Nonglycolytic Functions Of Pkm2mentioning

confidence: 99%

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Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

Tamada

Suematsu

Saya

2012

Clinical Cancer Research

207

199

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The M2 splice isoform of pyruvate kinase (PKM2), an enzyme that catalyzes the later step of glycolysis, is a key regulator of aerobic glycolysis (known as the Warburg effect) in cancer cells. Expression and low enzymatic activity of PKM2 confer on cancer cells the glycolytic phenotype, which promotes rapid energy production and flow of glycolytic intermediates into collateral pathways to synthesize nucleic acids, amino acids, and lipids without the accumulation of reactive oxygen species. PKM2 enzymatic activity has also been shown to be negatively regulated by the interaction with CD44 adhesion molecule, which is a cell surface marker for cancer stem cells. In addition to the glycolytic functions, nonglycolytic functions of PKM2 in cancer cells are of particular interest. PKM2 is induced translocation into the nucleus, where it activates transcription of various genes by interacting with and phosphorylating specific nuclear proteins, endowing cancer cells with a survival and growth advantage. Therefore, inhibitors and activators of PKM2 are well underway to evaluate their anticancer effects and suitability for use as novel therapeutic strategies.

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Section: Glycolytic Functions Of Pkm2mentioning

confidence: 99%

Section: Nonglycolytic Functions Of Pkm2mentioning

confidence: 99%

Section: Nonglycolytic Functions Of Pkm2mentioning

confidence: 99%

See 1 more Smart Citation

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

Tamada

Suematsu

Saya

2012

Clinical Cancer Research

207

199

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“…Murine BMDCs were prepared as previously described by us. 48,49 Human cDCs and pDCs were isolated from PBMCs or from tumor tissues with cDC and pDC isolation kits (Miltenyi Biotec, Auburn, CA, USA) according to the manufacturer's instructions. The purity of the isolated cells was over 90%.…”

Section: Materials and Methods Micementioning

confidence: 99%

“…48 Hybridizations with primary antibodies were carried out for 1 hour at room temperature in blocking buffer. The protein-antibody complexes were detected using peroxidase-conjugated secondary antibodies (Boehringer Mannheim, Mannheim, Germany) and enhanced chemiluminescence (Amersham, Buckinghamshire, UK).…”

Section: Western Blotting Analysesmentioning

confidence: 99%

TGF-β-associated miR-27a inhibits dendritic cell-mediated differentiation of Th1 and Th17 cells by TAB3, p38 MAPK, MAP2K4 and MAP2K7

Song

Zhang

et al. 2012

Genes Immun

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The alterations induced in dendritic cells (DCs) in the cancer microenvironment have not been extensively explored. We found that the tumor-associated factor TGF-b may selectively upregulate the expression of miR-27a via the SP1 transcription factor. Importantly, miR-27a altered the activity of NF-kB and MAPKs (mitogen-activated protein kinases) p38, JNK (c-Jun N-terminal kinases) and ERK (extracellular signal-regulated kinase 1/2). It influences the production of proinflammatory cytokines by targeting TAB3, p38 MAPK, MAP2K4 and MAP2K7. As a consequence, miR-27a hampered the DC-mediated differentiation of Th1 and Th17 cells in vitro and in vivo, but it promoted the DC-mediated accumulation of Tr1 (CD4 þ IL-10 þ ) and Treg (CD4 þ CD25 þ Foxp3 þ ) cells in vivo. The repeated infusion of miR-27a-engineered DCs into tumor tissues accelerated tumor growth, indicating that miR-27a is a potential target for tumor immunotherapy.

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Pyruvate kinase M2 is a novel diagnostic marker and predicts tumor progression in human biliary tract cancer

Dhar

Damink

Brindley

et al. 2012

Cancer

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Background and Aim The early diagnosis of biliary tract cancer (BTC) remains challenging and there are few effective therapies. We investigated whether the M2 isotype of pyruvate kinase (M2-PK), which serves as the key regulator of cellular energy metabolism in proliferating cells, could play a role in the diagnosis and therapy of BTC. Methods Plasma and bile M2-PK concentrations were measured by ELISA in 88 patients with BTC, 79 with benign biliary diseases and 17 healthy controls. M2-PK expression was sought in BTC tissue array by immunohistochemistry. The role of M2-PK in tumour growth, invasion and angiogenesis was evaluated in BTC cell lines by retrovirus-mediated M2-PK transfection and shRNA silencing techniques. Results Sensitivity (90.3%) and specificity (84.3%) of bile M2-PK for malignancy were significantly higher than those for plasma M2-PK and serum CA19-9. M2-PK expression was specific for cancer cells and correlated with microvessel density. M2-PK positivity was a significant independent prognostic factor by multivariable analysis. Transfection of M2-PK in a negatively expressed cell line (HuCCT-1cells) increased cell invasion whereas silencing in a M2-PK positive cell line (TFK cells) decreased tumour nodule formation and cellular invasion. A significant increase in endothelial tube formation was noted when supernatants from M2-PK transfected cells were added to an in vitro angiogenesis assay whereas supernatants from silenced cells negated tube formation. Conclusions Bile M2-PK is a novel tumour marker for BTC and correlates with tumour aggressiveness and poor outcome. shRNA mediated inhibition of M2-PK indicates the potential of M2-PK as a therapeutic target.

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Antigen Presentation by Dendritic Cells in Tumors Is Disrupted by Altered Metabolism that Involves Pyruvate Kinase M2 and Its Interaction with SOCS3

Cited by 45 publications

References 35 publications

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

Pyruvate Kinase M2: Multiple Faces for Conferring Benefits on Cancer Cells

TGF-β-associated miR-27a inhibits dendritic cell-mediated differentiation of Th1 and Th17 cells by TAB3, p38 MAPK, MAP2K4 and MAP2K7

Pyruvate kinase M2 is a novel diagnostic marker and predicts tumor progression in human biliary tract cancer

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