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Abstract
Accumulating evidence supports the existence of glioma stem cells (GSCs) and their critical role in the resistance to conventional treatments for glioblastoma multiforme (GBM). Differentiation therapy represents a promising alternative strategy against GBM by forcing GSCs to exit the cell cycle and reach terminal differentiation. In this study, we demonstrated that cAMP triggered neuronal differentiation and compromised the self-renewal capacity in GSCs. In addition, cAMP induced negative feedback to antagonize the differentiation process by activating β-catenin pathway. Suppression of β-catenin signaling synergized with cAMP activators to eliminate GSCs in vitro and extended the survival of animals in vivo. The cAMP/PKA pathway stabilized β-catenin through direct phosphorylation of the molecule and inhibition of GSK-3β. The activated β-catenin translocated into the nucleus and promoted the transcription of APELA and CARD16, which were found to be responsible for the repression of cAMP-induced differentiation in GSCs. Overall, our findings identified a negative feedback mechanism for cAMP-induced differentiation in GSCs and provided potential targets for the reinforcement of differentiation therapy for GBM.
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1 Sun Yat-sen University Cancer Center, Department of Neurosurgery/Neuro-oncology, Guangzhou, China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191); The Third Affiliated Hospital of Sun Yat-sen University Lingnan Hospital, Department of Neurosurgery, Guangzhou, China (GRID:grid.412558.f) (ISNI:0000 0004 1762 1794)
2 Sun Yat-sen University, Department of Pharmacology, Zhongshan School of Medicine, Guangzhou, China (GRID:grid.12981.33) (ISNI:0000 0001 2360 039X)
3 Guangdong Academy of Medical Sciences, Department of Pancreas Center, Guangdong Provincial People’s Hospital, Guangzhou, China (GRID:grid.410643.4)
4 Sun Yat-sen University Cancer Center, Department of Neurosurgery/Neuro-oncology, Guangzhou, China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191); Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191)
5 Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191); Sun Yat-sen University Cancer Center, Department of Pathology, Guangzhou, China (GRID:grid.488530.2) (ISNI:0000 0004 1803 6191)