GDNF Promotes Astrocyte Abnormal Proliferation and Migration Through the GFRα1/RET/MAPK/pCREB/LOXL2 Signaling Axis

Wang, Miaomiao; Han, Xiao; Zha, Wei; Wang, Xiaoyu; Liu, Liyun; Li, Zimu; Shi, Yefeng; Kan, Xugang; Gui, Weihua; Gao, Dayong; Zhang, Baole

doi:10.1007/s12035-022-02978-1

Cited by 7 publications

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“…Treating U251 and HA with testosterone modified their function and behavior (proliferation, invasion, and migration). The secretion of cytokines by U251 and the recruitment of pro-inflammatory macrophages contribute to inflammation maintenance necessary for glioma cells and astrocytes survival [9,14] and tumor growth [13]. Males expressing more testosterone than females may explain the higher mortality rate in males with glioblastoma compared to females.…”

Section: Discussionmentioning

confidence: 99%

“…GDNF was first isolated in 1993 by Lin et al and shown to contribute to brain cancer development [10]. Several studies have described the role of GDNF in central nervous system diseases such as brain cancer and Parkinson's disease [11][12][13][14]. Rodrigez-Lozano, DC et al, in 2019, reported that testosterone promotes glioblastoma cell proliferation, invasion, and migration [15].…”

Section: Introductionmentioning

confidence: 99%

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Testosterone upregulates glial cell line-derived neurotrophic factor (GDNF) and promotes neuroinflammation to enhance glioma cell survival and proliferation

Kanwore,

Guo

et al. 2023

Inflamm Regener

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Background Testosterone contributes to male organism development, such as bone density, muscle development, and fat repartition. Estrogen (derived from testosterone) also contributes to female reproductive system development. Here, we investigated the effect of testosterone on glioma cells and brain neuron inflammation essential for cancer development and progression. Methods The human astrocyte and glioma cell lines were treated with 6 ng/ml exogenous testosterone in vitro. We performed cell counting kit-8, transwell, and wound healing assays to determine the effect of testosterone on glioma cell proliferation, migration, and invasion. The glioma cells were injected into the xenograft and treated with 5 µl concentrated testosterone. Transcriptional suppression of glial cell line-derived neurotrophic factor (GDNF) was performed to evaluate brain neuron inflammation and survival. The tumor tissues were assessed by hematoxylin–eosin staining and immunohistochemistry. Results Testosterone upregulates GDNF to stimulate proliferation, migration, and invasion of glioma cells. Pathologically, the augmentation of GDNF and cyclophilin A contributed to neuroprotection when treated with testosterone. Our investigation showed that testosterone contributes to brain neuron and astrocyte inflammation through the upregulation of nuclear factor erythroid 2-related factor 2 (NRF2), glial fibrillary acid protein (GFAP), and sirtuin 5 (SIRT5), resulting in pro-inflammatory macrophages recruitments into the neural microenvironment. Mechanically, testosterone treatment regulates GDNF translocation from the glioma cells and astrocyte nuclei to the cytoplasm. Conclusion Testosterone upregulates GDNF in glioma cells and astrocytes essential for microglial proliferation, migration, and invasion. Testosterone contributes to brain tumor growth via GDNF and inflammation. Graphical Abstract The contribution of testosterone, macrophages, and astrocytes, in old neuron rescue, survival, and proliferation. During brain neuron inflammation, the organism activates and stimulates the neuron rescue through the enrichment of the old neuron microenvironment with growth factors such as GDNF, BDNF, SOX1/2, and MAPK secreted by the surrounding neurons and glial cells to maintain the damaged neuron by inflammation alive even if the axon is dead. The immune response also contributes to brain cell survival through the secretion of proinflammatory cytokines, resulting in inflammation maintenance. The rescued old neuron interaction with infiltrated macrophages contributes to angiogenesis to supplement the old neuron with more nutrients leading to metabolism activation and surrounding cell uncontrollable cell growth.

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Section: Discussionmentioning

confidence: 99%