All-trans retinoic acid inhibits glioblastoma progression and attenuates radiation-induced brain injury
Min Fu, Yiling Zhang, Bi Peng, Na Luo, Yuanyuan Zhang, Wenjun Zhu, Feng Yang, Ziqi Chen, Qiang Zhang, Qianxia Li, Xin Chen, Yuanhui Liu, Guoxian Long, Guangyuan Hu, Xiaohong Peng
Min Fu, Yiling Zhang, Bi Peng, Na Luo, Yuanyuan Zhang, Wenjun Zhu, Feng Yang, Ziqi Chen, Qiang Zhang, Qianxia Li, Xin Chen, Yuanhui Liu, Guoxian Long, Guangyuan Hu, Xiaohong Peng
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All-trans retinoic acid inhibits glioblastoma progression and attenuates radiation-induced brain injury

Abstract

Radiotherapy (RT) remains a primary treatment modality for glioblastoma (GBM), but it induces cellular senescence and is strongly implicated in GBM progression and RT-related injury. Recently, eliminating senescent cells has emerged as a promising strategy for treating cancer and for mitigating radiation-induced brain injury (RBI). Here, we investigated the impact of all-trans retinoic acid (RA) on radiation-induced senescence. The findings of this study revealed that RA effectively eliminated astrocytes, which are particularly prone to senescence after radiation, and that the removal of senescence-associated secretory phenotype factor–producing astrocytes inhibited GBM cell proliferation in vitro. Moreover, RA-mediated clearance of senescent cells improved survival in GBM-bearing mice and alleviated radiation-induced cognitive impairment. Through RNA sequencing, we found that the AKT/mTOR/PPARγ/Plin4 signaling pathway is involved in RA-mediated clearance of senescent cells. In summary, these results suggest that RA could be a potential senolytic drug for preventing GBM progression and improving RBI.

Authors

Min Fu, Yiling Zhang, Bi Peng, Na Luo, Yuanyuan Zhang, Wenjun Zhu, Feng Yang, Ziqi Chen, Qiang Zhang, Qianxia Li, Xin Chen, Yuanhui Liu, Guoxian Long, Guangyuan Hu, Xiaohong Peng

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Figure 4

RA alleviates cognitive impairment and ameliorates RBI.

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RA alleviates cognitive impairment and ameliorates RBI. (A) Timeline of ...
(A) Timeline of the RA intervention and tests. (B and C) The movement trajectory (B) and total distance traveled (C) of mice from different groups in the OFT. Ctrl, control. (D) Plot represents recognition index of new objects of mice from different groups in the NOR test. (E) Representative TEM images of sections from mice in different groups. Scale bars: 500 nm. (F) Brain sections were stained with Luxol fast blue. Scale bars: 50 μm. (G) The mean intensity of the cortex in the different groups was analyzed. (H) The image shows the areas analyzed by performing immunocytochemical staining for MBP in the cortex of mice. Scale bars: 100 μm. (I) Graphs showing the intensity of MBP staining in the cortex. (J) Western blotting for senescence markers after 60 days. (K) RNA-seq analysis of genes (27) exhibiting significant changes in expression after irradiation that were rescued by RA inhibition. (L and M) ELISA analysis of Ccl8 and Ccl2 protein levels in radiated brain. (N–S) qRT-PCR analysis of SASP gene mRNA levels in brain after radiation. n = 8–9 mice per group for NOR and OFT analyses; n = 4–6 mice per group for Western blotting, ELISA, and qRT-PCR analyses; n = 3 mice per group for the RNA-seq and LFB and IHC staining. Each dot represents 1 mouse. Data are presented as mean ± SEM and were analyzed by 2-way ANOVA with Tukey’s multiple-comparison test. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001. Four groups were established for in vivo study: Ctrl, control mice treated with 450 μg/kg (RA), irradiated mice (RT), and irradiated mice treated with 450 μg/kg RA (RT+RA).