Abstract
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.
Highlights
An alternative strategy to conventional anticancer therapies has been to target the specific metabolism of cancer cells to eliminate the tumor
Compared with spheroids that contain rat neural stem cells (NSCs), the expression of PKM was increased in spheroids that contained cancer stem cells (CSCs) derived from the glioma cell line C6 or from two ethylnitrosourea (ENU)-induced rat gliomas (P7 and M7) obtained as described earlier[21] (Figure 1a)
The downregulation of Pyruvate kinase isoform 2 (PKM2), but not that of PKM1, abrogated the DCA-induced pyruvate kinase (PK) activity in glioma spheroids. It did not affect the PKM activity in NSC. We found another difference between cancer and NSCs as PKM2 was phosphorylated in glioma spheroids and this phosphorylation decreased after DCA treatment
Summary
An alternative strategy to conventional anticancer therapies has been to target the specific metabolism of cancer cells to eliminate the tumor. We found another difference between cancer and NSCs as PKM2 was phosphorylated in glioma spheroids and this phosphorylation decreased after DCA treatment. Immunocytochemical analyses of the neurospheres confirmed these results (Supplementary Figure S5), suggesting that DCA induced cell differentiation of CSCs contained in glioma spheroids into neural progenitor phenotypes.
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