The Anti-Warburg Effect Elicited by the cAMP-PGC1α Pathway Drives Differentiation of Glioblastoma Cells into Astrocytes

Fan Xing, Yizhao Luan, Jing Cai, Sihan Wu, Jialuo Mai, Jiayu Gu, Haipeng Zhang, Kai Li, Yuan Lin, Xiao Xiao, Jiankai Liang, Yuan Li, Wenli Chen, Yaqian Tan, Longxiang Sheng, Bingzheng Lu, Wanjun Lu, Mingshi Gao, Pengxin Qiu, Xingwen SuWei Yin, Jun Hu, Zhongping Chen, Ke Sai, Jing Wang, Furong Chen, Yinsheng Chen, Shida Zhu, Dongbing Liu, Shiyuan Cheng, Zhi Xie, Wenbo Zhu, Guangmei Yan

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Glioblastoma multiforme (GBM) is among the most aggressive of human cancers. Although differentiation therapy has been proposed as a potential approach to treat GBM, the mechanisms of induced differentiation remain poorly defined. Here, we established an induced differentiation model of GBM using cAMP activators that specifically directed GBM differentiation into astroglia. Transcriptomic and proteomic analyses revealed that oxidative phosphorylation and mitochondrial biogenesis are involved in induced differentiation of GBM. Dibutyryl cyclic AMP (dbcAMP) reverses the Warburg effect, as evidenced by increased oxygen consumption and reduced lactate production. Mitochondrial biogenesis induced by activation of the CREB-PGC1α pathway triggers metabolic shift and differentiation. Blocking mitochondrial biogenesis using mdivi1 or by silencing PGC1α abrogates differentiation; conversely, overexpression of PGC1α elicits differentiation. In GBM xenograft models and patient-derived GBM samples, cAMP activators also induce tumor growth inhibition and differentiation. Our data show that mitochondrial biogenesis and metabolic switch to oxidative phosphorylation drive the differentiation of tumor cells.

Original languageEnglish (US)
Pages (from-to)468-481
Number of pages14
JournalCell Reports
Volume18
Issue number2
DOIs
StatePublished - Jan 10 2017
Externally publishedYes

Keywords

  • cAMP
  • cyclic adenosine monophosphate
  • glioblastoma
  • glycolysis
  • induced differentiation
  • metabolic reprogramming
  • mitochondrial biogenesis
  • oxidative phosphorylation
  • PGC1α
  • PPARγ coactivator-1α
  • Warburg effect

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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