Department of Neurosurgery/Neuro-oncology, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
Cell Death Dis. 2022 May 24;13(5):493. doi: 10.1038/s41419-022-04957-9.
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.
越来越多的证据支持神经胶质瘤干细胞（GSCs）的存在及其在胶质母细胞瘤（GBM）对常规治疗的耐药性中的关键作用。分化治疗通过迫使 GSCs 退出细胞周期并达到终末分化，代表了一种对抗 GBM 的有前途的替代策略。在这项研究中，我们证明 cAMP 触发神经元分化并损害 GSCs 的自我更新能力。此外，cAMP 通过激活β-连环蛋白途径诱导负反馈来拮抗分化过程。抑制β-连环蛋白信号与 cAMP 激活剂协同作用，可在体外消除 GSCs，并延长体内动物的存活时间。cAMP/PKA 途径通过直接磷酸化该分子和抑制 GSK-3β 来稳定β-连环蛋白。激活的β-连环蛋白易位到细胞核，并促进 APELA 和 CARD16 的转录，这两种转录物被发现负责抑制 GSCs 中 cAMP 诱导的分化。总的来说，我们的研究结果确定了 GSCs 中 cAMP 诱导分化的负反馈机制，并为强化 GBM 的分化治疗提供了潜在的靶点。
