Control of glioma cell death and differentiation by PKM2-Oct4 interaction.
Glioma stem cells are highly resistant to cell death and as such are supposed to contribute to tumor recurrence by eluding anticancer treatments. Here, we show that spheroids that contain rat neural stem cells (NSCs) or rat glioma stem cells (cancer stem cells, CSCs) express isoforms 1 and 2 of pyruvate kinase (PKM1 and PKM2); however, the expression of PKM2 is considerably higher in glioma spheroids. Silencing of PKM2 enhances both apoptosis and differentiation of rat and human glioma spheroids. We establish that PKM2 was implicated in glioma spheroid differentiation through its interaction with Oct4, a major regulator of self-renewal and differentiation in stem cells. The small molecule Dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, increases the amount of PKM2/Oct4 complexes and thus inhibited Oct4-dependent gene expression. Taken together, our results highlight a new molecular pathway through which PKM2 can manage gliomagenesis via the control of glioma stemness by Oct4.
1] UMR 892 INSERM, 6299 CNRS, Equipe Labellisée (Ligue contre le Cancer), Nantes, France [2] Faculté de Médecine, Université de Nantes, Nantes, France [3].
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Morfouace
1] UMR 892 INSERM, 6299 CNRS, Equipe Labellisée (Ligue contre le Cancer), Nantes, France [2] Faculté de Médecine, Université de Nantes, Nantes, France [3] Institut de Cancérologie de l'Ouest, Nantes-Saint Herblain, Nantes, France.
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Lalier
1] UMR 892 INSERM, 6299 CNRS, Equipe Labellisée (Ligue contre le Cancer), Nantes, France [2] Faculté de Médecine, Université de Nantes, Nantes, France [3] CHU Hotel-Dieu, Nantes, France.
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Oliver
1] UMR 892 INSERM, 6299 CNRS, Equipe Labellisée (Ligue contre le Cancer), Nantes, France [2] Faculté de Médecine, Université de Nantes, Nantes, France.
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Cheray
1] UMR 892 INSERM, 6299 CNRS, Equipe Labellisée (Ligue contre le Cancer), Nantes, France [2] Faculté de Médecine, Université de Nantes, Nantes, France.
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Pecqueur
1] UMR 892 INSERM, 6299 CNRS, Equipe Labellisée (Ligue contre le Cancer), Nantes, France [2] Faculté de Médecine, Université de Nantes, Nantes, France.
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Cartron
1] UMR 892 INSERM, 6299 CNRS, Equipe Labellisée (Ligue contre le Cancer), Nantes, France [2] Faculté de Médecine, Université de Nantes, Nantes, France [3] Institut de Cancérologie de l'Ouest, Nantes-Saint Herblain, Nantes, France.
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Vallette
D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000166:cytology* / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D050814:Octamer Transcription Factor-3 / Q000235:genetics / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
D050814:Octamer Transcription Factor-3; D011770:Pyruvate Kinase