Nuclear translocation of PKM2/AMPK complex sustains cancer stem cell populations under glucose restriction stress

Yang, Yi; Chien, Ming Hsien; Liu, Hsin Yi; Chang, Yu‐Chan; Chen, Chi Kuan; Lee, Wei Jiunn; Kuo, Tsun-Cheng; Hsiao, Michael; Hua, Kuo Tai; Cheng, Tsu‐Yao

doi:10.1016/j.canlet.2018.01.075

Cited by 60 publications

(46 citation statements)

References 45 publications

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“…Pyruvate kinase isoform M2 (PKM2), the key rate-limiting enzyme catalyzing the final step of glycolysis, plays a critical role in tumor glucose metabolism and is highly expressed in various types of human cancers (9,10). PKM2 has been proposed to play a vital role in maintaining the metabolism program (11,12), promoting proliferation (11), resistance to genotoxic treatments (13), and metastasis (14) and inducing cancer stem-like cell properties (15) in many types of cancer. Besides its roles in regulating the cancer cell, PKM2 has been proven to contribute to tumor microenvironment, such as reducing lactate production, increasing OXPHOS (9,16).…”

Section: Introductionmentioning

confidence: 99%

Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling

Guo

Zhang

et al. 2020

Front. Oncol.

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Pyruvate kinase M2 (PKM2) is a key enzyme of glycolysis, which is highly expressed in many tumor cells, and has emerged as an important player in tumor progression and metastasis. However, the functional roles of PKM2 in tumor metastasis remain elusive. Here we showed that PKM2 promoted prostate cancer metastasis via extracellularregulated protein kinase (ERK)-cyclooxygenase (COX-2) signaling. Based on public databases, we found that PKM2 expression was upregulated in prostate cancer and positively associated with tumor metastasis. Further analysis showed that PKM2 promoted prostate cancer cell migration/invasion and epithelial-mesenchymal transition (EMT) through upregulation of COX-2. Mechanistically, PKM2 interacted with ERK1/2 and regulated its phosphorylation, leading to phosphorylation of transcription factor c-Jun, downstream of ERK1/2, to activate COX-2 transcription by IP and ChIP assay, while inhibition of COX-2 significantly reversed the promotion effect of PKM2 on tumor metastasis in vivo. Taken together, our results suggest that a novel of PKM2-ERK1/2c-Jun-COX-2 axis is a potential target in controlling prostate cancer metastasis.

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Section: Introductionmentioning

confidence: 99%

Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling

Guo

Zhang

et al. 2020

Front. Oncol.

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“…In addition, PKM2 in nucleus has been suggested as a novel modulator of genomic instability, cancer stemness, and cancer-associated inflammation, etc. [21][22][23] Therefore, reduction of nuclear PKM2 could be prioritized as a therapeutic strategy in anticancer research. Posttranslational protein modification is the best understood mechanism for regulating subcellular localization of PKM2, such as phosphorylation, acetylation, succinylation, O-GlcNAcylation, and so on [44][45][46][47].…”

Section: Discussionmentioning

confidence: 99%

“…Warburg effect or aerobic glycolysis is a prominent metabolic feature of cancer cells, and PKM2 plays a key role in such metabolic reshuffle [19,20]. Recently years, PKM2 has been extensively studied in non-glycolytic activity and exhibits various biological functions in tumor progression [21][22][23], for example, nuclear dimer PKM2 as a protein tyrosine kinase directly phosphorylates the signal transducer and activator of transcription 3 (STAT3) at T705, thereby contributing to drive cancer cell proliferation [24]. Moreover, PKM2 in tumor cells mediates resistance acquisition to various chemotherapeutic drugs, such as gefitinib [25,26].…”

Section: Introductionmentioning

confidence: 99%

The eEF2 kinase-induced STAT3 inactivation inhibits lung cancer cell proliferation by phosphorylation of PKM2

Xiao

Xie

et al. 2020

Cell Commun Signal

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Background: Eukaryotic elongation factor-2 kinase (eEF2K) is a Ca 2+ /calmodulin (CaM)-dependent protein kinase that inhibits protein synthesis. However, the role of eEF2K in cancer development was reported paradoxically and remains to be elucidated. Methods: Herein, A549 cells with eEF2K depletion or overexpression by stably transfected lentivirus plasmids were used in vitro and in vivo study. MTT and colony assays were used to detect cell proliferation and growth. Extracellular glucose and lactate concentration were measured using test kit. Immunoblot and co-immunoprecipitation assays were used to examine the molecular biology changes and molecular interaction in these cells. LC-MS/MS analysis and [γ-32 P] ATP kinase assay were used to identify combining protein and phosphorylation site. Nude mice was utilized to study the correlation of eEF2K and tumor growth in vivo. Results: We demonstrated that eEF2K inhibited lung cancer cells proliferation and affected the inhibitory effects of EGFR inhibitor gefitinib. Mechanistically, we showed that eEF2K formed a complex with PKM2 and STAT3, thereby phosphorylated PKM2 at T129, leading to reduced dimerization of PKM2. Subsequently, PKM2 impeded STAT3 phosphorylation and STAT3-dependent c-Myc expression. eEF2K depletion promoted the nuclear translocation of PKM2 and increased aerobic glycolysis reflected by increased lactate secretion and glucose. Conclusions: Our findings define a novel mechanism underlying the regulation of cancer cell proliferation by eEF2K independent of its role in protein synthesis, disclosing the diverse roles of eEF2K in cell biology, which lays foundation for the development of new anticancer therapeutic strategies.

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“…Notably, AMP-activated kinase (AMPK) is a cellular energy sensor which modulates metabolism in cells lacking nutrients [35]. There are reports indicating an involvement of AMPK in mechanisms adapting CSCs to hypoxia and nutrient limitation [36,37]. The other energy metabolism-related enzyme, hexokinase 2 (HK2), functions in CSCs as an activator of glycolysis and anti-apoptotic factor conferring chemoresistance [38].…”

Section: Resistance Of Cscs To Therapeutics Immune Attack and Stresmentioning

confidence: 99%

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

Kabakov

Yakimova

Matchuk

2020

Cells

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Cancer stem cells (CSCs) are a great challenge in the fight against cancer because these self-renewing tumorigenic cell fractions are thought to be responsible for metastasis dissemination and cases of tumor recurrence. In comparison with non-stem cancer cells, CSCs are known to be more resistant to chemotherapy, radiotherapy, and immunotherapy. Elucidation of mechanisms and factors that promote the emergence and existence of CSCs and their high resistance to cytotoxic treatments would help to develop effective CSC-targeting therapeutics. The present review is dedicated to the implication of molecular chaperones (protein regulators of polypeptide chain folding) in both the formation/maintenance of the CSC phenotype and cytoprotective machinery allowing CSCs to survive after drug or radiation exposure and evade immune attack. The major cellular chaperones, namely heat shock proteins (HSP90, HSP70, HSP40, HSP27), glucose-regulated proteins (GRP94, GRP78, GRP75), tumor necrosis factor receptor-associated protein 1 (TRAP1), peptidyl-prolyl isomerases, protein disulfide isomerases, calreticulin, and also a transcription heat shock factor 1 (HSF1) initiating HSP gene expression are here considered as determinants of the cancer cell stemness and potential targets for a therapeutic attack on CSCs. Various approaches and agents are discussed that may be used for inhibiting the chaperone-dependent development/manifestations of cancer cell stemness.

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Nuclear translocation of PKM2/AMPK complex sustains cancer stem cell populations under glucose restriction stress

Cited by 60 publications

References 45 publications

Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling

Pyruvate Kinase M2 Promotes Prostate Cancer Metastasis Through Regulating ERK1/2-COX-2 Signaling

The eEF2 kinase-induced STAT3 inactivation inhibits lung cancer cell proliferation by phosphorylation of PKM2

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

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