Anti-Warburg effect elicited by mitochondrial biogenesis drives differentiation of glioblastoma cells into astroglial cells

Glioblastoma (GBM) is among the most aggressive of human cancers. Although differentiation therapy has been proposed to be potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established the induced differentiation model of GBM by using cAMP activators, which specifically directed GBM into astroglia. Next, transcriptomic and proteomic analyses uncovered oxidative phosphorylation and mitochondrial biogenesis were involved in induced differentiation of GBM. Further investigation showed dbcAMP reversed Warburg effect evidenced by increase of oxygen consumption and reduction of lactate production. Stimulated mitochondrial biogenesis downstream of CREB/PGC1a pathway triggered metabolic shift and differentiation. Blocking mitochondrial biogenesis by mdivi1 or silencing PGC1a abrogated differentiation, reversely over-expression of PGC1a elicited differentiation. In GBM xenograft models and patient-derived GBM samples, cAMP activators also induced tumor growth inhibition and differentiation. This study shows mitochondrial biogenesis and metabolic switch to oxidative phosphorylation drive the differentiation process of tumor cells. Overall design: mRNA profiles of cell line DBTRG-05MG after 0h, 6h, 12h, 24h and 48h of dbcAMP treatment

5

Xing F, Luan Y, Cai J, Wu S, Mai J, Gu J, Zhang H, Li K, Lin Y, Xiao X, Liang J, Li Y, Chen W, Tan Y, Sheng L, Lu B, Lu W, Gao M, Qiu P, Su X, Yin W, Hu J, Chen Z, Sai K, Wang J, Chen F, Chen Y, Zhu S, Liu D, Cheng S, Xie Z, Zhu W, Yan G