Pyruvate Kinase M2 in Blood Circulation Facilitates Tumor Growth by Promoting Angiogenesis

Li, Liangwei; Zhang, Yinwei; Qiao, Jingjuan; Yang, Jenny J.; Liu, Zhi-Ren

doi:10.1074/jbc.m114.576934

Cited by 74 publications

(80 citation statements)

References 21 publications

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“…Our previous study demonstrated that extracellular PKM2 facilitates tumor growth by promoting angiogenesis. The extracellular PKM2 promotes angiogenesis by facilitating endothelial cell migration and extracellular matrix (ECM) attachment . High serum levels of PKM2 are also detected in patients of various inflammatory diseases, indicating a potential association of release of extracellular PKM2 with inflammations.…”

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confidence: 99%

PKM2 released by neutrophils at wound site facilitates early wound healing by promoting angiogenesis

Zhang

Liu

et al. 2016

Wound Repair Regeneration

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Neutrophils infiltration/activation following wound induction marks the early inflammatory response in wound repair. However, the role of the infiltrated/activated neutrophils in tissue regeneration/proliferation during wound repair is not well understood. Here, we report that infiltrated/activated neutrophils at wound site release pyruvate kinase M2 (PKM2) by its secretive mechanisms during early stages of wound repair. The released extracellular PKM2 facilitates early wound healing by promoting angiogenesis at wound site. Our studies reveal a new and important molecular linker between the early inflammatory response and proliferation phase in tissue repair process.

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confidence: 99%

PKM2 released by neutrophils at wound site facilitates early wound healing by promoting angiogenesis

Zhang

Liu

et al. 2016

Wound Repair Regeneration

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“…Recombinant pyruvate kinase M2 (rPKM2) was produced by Dr. Zhi-Ren Liu's group according to the published protocol [20,21]. rPKM2 (160 ng/kg) was administered intranasally according to established procedures every other day starting 24 h after stroke until the animals were sacrificed [22].…”

Section: Drug Administrationmentioning

confidence: 99%

“…PKM2 can regulate gene transcription MEK5 by phosphorylating STAT3, which in turn activates numerous transcriptional factors to regulate cell proliferation, differentiation, migration, and survival [11,12,19]. PKM2 greatly promotes tumorous angiogenesis through enhancing the endothelial cell migration and extracellular matrix attachment [20]. PKM2 was recently found to be released by neutrophils at peripheral wound sites and to facilitate early wound healing by promoting angiogenesis [21].…”

Section: Introductionmentioning

confidence: 99%

Pyruvate Kinase M2 Increases Angiogenesis, Neurogenesis, and Functional Recovery Mediated by Upregulation of STAT3 and Focal Adhesion Kinase Activities After Ischemic Stroke in Adult Mice

et al. 2018

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Ischemic stroke remains a serious threat to human life. Generation of neuronal and vascular cells is an endogenous regenerative mechanism in the adult brain, which may contribute to tissue repair after stroke. However, the regenerative activity is typically insufficient for significant therapeutic effects after brain injuries. Pyruvate kinase isoform M2 (PKM2) is a key regulator for energy metabolism. PKM2 also has nonmetabolic roles involving regulations of gene expression, cell proliferation, and migration in cancer cells as well as noncancerous cells. In a focal ischemic stroke mouse model, recombinant PKM2 (rPKM2) administration (160 ng/kg, intranasal delivery) at 1 h after stroke showed the significant effect of a reduced infarct volume of more the 60%. Delayed treatment of rPKM2, however, lost the acute neuroprotective effect. We then tested a novel hypothesis that delayed treatment of PKM2 might show proregenerative effects for long-term functional recovery and this chronic action could be mediated by its downstream STAT3 signaling. rPKM2 (160 ng/kg) was delivered to the brain using noninvasive intranasal administration 24 h after the stroke and repeated every other day. Western blot analysis revealed that, 7 days after the stroke, the levels of PKM2 and phosphorylated STAT3 and the expression of angiogenic factors VEGF, Ang-1, and Tie-2 in the peri-infarct region were significantly increased in the rPKM2 treatment group compared with those of the stroke vehicle group. To label proliferating cells, 5-bromo-2'-deoxyuridine (BrdU, 50 mg/kg, i.p.) was injected every day starting 3 days after stroke. At 14 days after stroke, immunohistochemistry showed that rPKM2 increased cell homing of doublecortin (DCX)-positive neuroblasts to the ischemic cortex. In neural progenitor cell (NPC) cultures, rPKM2 (0.4-4 nM) increased the expression of integrin β1 and the activation/phosphorylation of focal adhesion kinase (FAK). A mediator role of FAK in PKM2-promoted cell migration was verified in FAK-knockout fibroblast cultures. In the peri-infarct region of the brain, increased numbers of Glut-1/BrdU and NeuN/BrdU double-positive cells indicated enhanced angiogenesis and neurogenesis, respectively, compared to stroke vehicle mice. Using Laser Doppler imaging, we observed better recovery of the local blood flow in the peri-infarct region of rPKM2-treated mice 14 days after stroke. Meanwhile, rPKM2 improved the sensorimotor functional recovery measured by the adhesive removal test. Inhibiting the STAT3 phosphorylation/activation by the STAT3 inhibitor, BP-1-102 (3 mg/kg/day, o.g.), abolished all beneficial effects of rPKM2 in the stroke mice. Taken together, this investigation provides the first evidence demonstrating that early treatment of rPKM2 shows an acute neuroprotective effect against ischemic brain damage, whereas delayed rPKM2 treatment promotes regenerative activities in the poststroke brain leading to better functional recovery. The underlying mechanism involves activation of the STAT3 and FAK signals in the pos...

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“…26,27,33,34 Specifically PKM2, which is the rate-limiting enzyme of glycolysis, controlling the conversion of phosphoenolpyruvate to pyruvate, has recently been shown to promote angiogenesis in ECs. 24,25 Indeed, we found that knockdown of PKM2 resulting in impaired angiogenic sprouting and JMJD8 stimulates the formation of pyruvate in ECs. The precise mechanism of how JMJD8 regulates PKM2 is currently unknown.…”

Section: Discussionmentioning

confidence: 92%

“…However, N-terminal deletion of aa 1 to 200 of JMJD8 (Δ2 construct) did prevent binding to PKM2 ( Figure IVA and IVB in the online-only Data Supplement), suggesting that PKM2 interaction with JMJD8 occurs in the region between aa 63 and 124. Interestingly, PKM2 has recently been shown to promote angiogenesis in ECs, 24,25 suggesting that cytoplasmic JMJD8 could regulate angiogenesis by controlling metabolic functions of EC, a mechanism which was recently shown to play a key role in regulating angiogenesis. 26,27 …”

Section: Jmjd8 Has An Extranuclear Localization and Binds To Pkm2 In Ecsmentioning

confidence: 99%

JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells

Boeckel

Derlet

Glaser

et al. 2016

ATVB

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Pyruvate Kinase M2 in Blood Circulation Facilitates Tumor Growth by Promoting Angiogenesis

Cited by 74 publications

References 21 publications

PKM2 released by neutrophils at wound site facilitates early wound healing by promoting angiogenesis

PKM2 released by neutrophils at wound site facilitates early wound healing by promoting angiogenesis

Pyruvate Kinase M2 Increases Angiogenesis, Neurogenesis, and Functional Recovery Mediated by Upregulation of STAT3 and Focal Adhesion Kinase Activities After Ischemic Stroke in Adult Mice

JMJD8 Regulates Angiogenic Sprouting and Cellular Metabolism by Interacting With Pyruvate Kinase M2 in Endothelial Cells

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