Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells

Kefas, Benjamin; Comeau, Laurey; Erdle, Nicholas; Montgomery, Emmitt; Amos, Samson; Purow, Benjamin

doi:10.1093/neuonc/noq080

Cited by 212 publications

(175 citation statements)

References 37 publications

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“…Mutations in these regions render the 3Ј-UTR unresponsive to treatment with miR-7 (20,27). (21,28). Cell extracts were performed as detailed previously (13) and subjected to SDS-PAGE and immunoblot analysis.…”

Section: Methodsmentioning

confidence: 99%

“…For Usp18, pituitary gland specific factor 1a (PGSF1a), pri-miR-7-2 and heterogeneous nuclear ribonucleoprotein K (hnRNPK), specific primers were used. All samples were analyzed with an Applied Biosystems (StepOnePlus) realtime PCR system and normalization to U6B small RNA (28). Data analysis was carried out using StepOne Software v2.1 (Applied Biosystems).…”

Section: Methodsmentioning

confidence: 99%

“…Protein Extraction and Quantification-Cells were lysed in 1ϫ-cell lysis buffer containing 0.2% SDS and complete protease inhibitors (Cell Signaling Technology, Denvers, MA) (28). Protein assay was performed using bicinchoninic acid (Bio-Rad) kit according to manufacturer's instructions and as previously described (21,29,30).…”

Section: Methodsmentioning

confidence: 99%

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Usp18 Regulates Epidermal Growth Factor (EGF) Receptor Expression and Cancer Cell Survival via MicroRNA-7

Duex

Comeau

Sorkin

et al. 2011

Journal of Biological Chemistry

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Epidermal growth factor receptor (EGFR) is involved in development and progression of many human cancers. We have previously demonstrated that the ubiquitin-specific peptidase Usp18 (Ubp43) is a potent regulator of EGFR protein expression. Here we report that the 3-untranslated region (3-UTR) of the EGFR message modulates RNA translation following cell treatment with Usp18 siRNA, suggesting microRNA as a possible mediator. Given earlier evidence of EGFR regulation by the microRNA miR-7, we assessed whether miR-7 mediates Usp18 siRNA effects. We found that Usp18 depletion elevates miR-7 levels in several cancer cell lines because of a transcriptional activation and/or mRNA stabilization of miR-7 host genes and that miR-7 acts downstream of Usp18 to regulate EGFR mRNA translation via the 3-UTR. Also, depletion of Usp18 led to a decrease in protein levels of other known oncogenic targets of miR-7, reduced cell proliferation and soft agar colony formation, and increased apoptosis. Notably, all of these phenotypes were reversed by a specific inhibitor of miR-7. Thus, our findings support a model in which Usp18 inhibition promotes upregulation of miR-7, which in turn inhibits EGFR expression and the tumorigenic activity of cancer cells.Despite advances in cancer treatments, improvement of overall patient survival remains poor. One of the primary reasons for this low success is the inherent complexity of oncogenic pathways such as those driven by the epidermal growth factor (EGF) 5 receptor (EGFR). EGFR is a member of the receptor tyrosine kinase (RTK) family. Upon binding of ligand, EGFR autophosphorylates at tyrosine residues and triggers an intracellular signal transduction cascade, which ultimately promotes cellular survival and division (1, 2). Dysregulation of EGFR and downstream signaling events is found in a multitude of tumor types (3-6). Therefore, targeting the tyrosine kinase activity of EGFR with small molecule inhibitors or targeting EGFR with antibodies has been a focus in the treatment of several tumors, including brain (glioblastoma), cervical, lung, and head and neck (squamous cell carcinoma). However, this strategy has resulted in minimal success. A major limitation of these approaches is that tumor cells eventually develop resistance to the current therapeutics. The resistance develops through increased ligand expression, additional somatic mutations in the EGFR tyrosine kinase domain, and increased heterodimerization with other RTKs (3, 7-9).As an alternative to developing approaches to directly inhibit EGFR signaling, our recent efforts focused on identifying allosteric modulators of EGFR protein levels. Inhibition of these modulators has the potential to significantly decrease EGFR protein levels irrespective of ligand levels or EGFR mutational status. Using a library of small interfering RNAs (siRNAs) that target deubiquitinase enzymes (DUBs), a class of proteins known to regulate receptor trafficking and expression (10 -12), we identified a number of candidate proteins which regulate EGFR prote...

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Usp18 Regulates Epidermal Growth Factor (EGF) Receptor Expression and Cancer Cell Survival via MicroRNA-7

Duex

Comeau

Sorkin

et al. 2011

Journal of Biological Chemistry

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“…MiR-326 has been shown to target PKM2 and suppress cell growth. As a result, in glioblastoma cell lines, the upregulation of PKM2 correlates with low levels of miR-326 [43]. Likewise, miR-122 targets PKM2 and inhibits hepatocellular carcinoma (HCC) proliferation.…”

Section: Functions Of Mirnas In Glycolysismentioning

confidence: 99%

miRNAs link metabolic reprogramming to oncogenesis

Hatziapostolou¹,

Polytarchou²,

Iliopoulos

2013

Trends in Endocrinology & Metabolism

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“…PKM2 has also shown contribution to gefitinib resistance via up‐regulation of STAT3 activation in colorectal cancer 24. Depletion of PKM2 led to apoptosis or sensitivity of several tumour cells to chemotherapy 25, 26. However, whether PKM2‐induced STAT3 phosphorylation plays a significant role in the regulation of THP sensitivity in bladder cancer cells remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Down‐regulation of PKM2 enhances anticancer efficiency of THP on bladder cancer

Tao

Tang

et al. 2018

J Cellular Molecular Medi

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Pyruvate kinase M2 (PKM2) regulates the final step of glycolysis levels that are correlated with the sensitivity of anticancer chemotherapeutic drugs. THP is one of the major drugs used in non‐muscle‐invasive bladder cancer instillation chemotherapy. However, low response ratio of THP (19.7%) treatment to human genitourinary tumours using collagen gel matrix has been observed. This study aims to investigate the effect of down‐regulation of PKM2 on THP efficiency. Via inhibitor or siRNA, the effects of reduced PKM2 on the efficiency of THP were determined in 2 human and 1 murine bladder cancer cell lines, using MTT, cologenic and fluorescence approaches. Molecular mechanisms of PKM2 on THP sensitization were explored by probing p‐AMPK and p‐STAT3 levels via WB. Syngeneic orthotopic bladder tumour model was applied to evaluate this efficiency in vivo, analysed by Kaplan‐Meier survival curves, body and bladder weights plus immunohistochemistric tumour biomarkers. PKM2 was overexpressed in bladder cancer cells and tissues, and down‐regulation of PKM2 enhanced the sensitivity of THP in vitro. Activation of AMPK is essential for THP to exert anti‐bladder cancer activities. On the other hand, down‐regulating PKM2 activates AMPK and inhibits STAT3, correlated with THP sensitivity. Compared with THP alone (400 μmol L−1, 50 μL), the combination with metformin (60 mmol L−1, 50 μL) stopped growth of bladder cancer completely in vivo (combination group VS normal group P = .078). Down‐regulating the expression of PKM2 enhances the anticancer efficiency of THP. This study provides a new insight for improving the chemotherapeutic effect of THP.

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Pyruvate kinase M2 is a target of the tumor-suppressive microRNA-326 and regulates the survival of glioma cells

Cited by 212 publications

References 37 publications

Usp18 Regulates Epidermal Growth Factor (EGF) Receptor Expression and Cancer Cell Survival via MicroRNA-7

Usp18 Regulates Epidermal Growth Factor (EGF) Receptor Expression and Cancer Cell Survival via MicroRNA-7

miRNAs link metabolic reprogramming to oncogenesis

Down‐regulation of PKM2 enhances anticancer efficiency of THP on bladder cancer

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