CCL2-targeted ginkgolic acid exerts anti-glioblastoma effects by inhibiting the JAK3-STAT1/PI3K-AKT signaling pathway

Chen, Xi; Zhu, Mingwei; Zou, Xiaomeng; Mao, Yingxuan; Niu, Jiamei; Jiang, Jian; Dong, Tianxiu; Shi, Ying; Yang, Xiuhua; Liu, Pengfei

doi:10.1016/j.lfs.2022.121174

Cited by 7 publications

(3 citation statements)

References 39 publications

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“…Ginkgolic acid is an alkyl phenolic constituent extracted from the Ginkgo biloba [28]. Previous studies have shown that GA possesses numerous biological activities, including anti-inflammatory, anti-tumor, and anti-bacterial [35] [36]. Here, we demonstrated that GA inhibited necroptosis, inflammatory responses, and endothelial damage in vascular tissues.…”

Section: Discussionmentioning

confidence: 51%

Hypoxia-mediated SUMOylation of FADD exacerbates endothelial cell injury via the RIPK1-RIPK3-MLKL sig-naling axis

Yu,

Yang,

Wen

et al. 2024

Preprint

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Vascular endothelial cells are the predominant cell type in the cardiovascular system, and endothelial dysfunction and death fol-lowing hypoxic injury lead to vascular lesions and play an essential role in the progression of cardiovascular disease. However, the mechanisms and specific interventions of vascular endothelial cell injury under hypoxia remain unclear. Here, we reported that hypox-ia induces the development of necroptosis and exacerbates in-flammatory injury in vascular endothelial cells in vivo and in vitro. We identified FADD as a critical regulator of hypoxia-mediated necroptosis, and the knockdown of FADD effectively reversed hy-poxia-induced necroptosis. Mechanistically, hypoxia affected pro-tein conformation through SUMOylation of FADD and competitively inhibited its ubiquitination, leading to an increase in protein half-life and protein level of FADD. On the other hand, SUMOylation in-creased the interaction between FADD and RIPK1 and induced the formation of the FADD-RIPK1-RIPK3 complex, thereby promoting necroptosis in vascular endothelial cells. The SUMOylation inhibi-tor ginkgolic acid (GA) notably reduced hypoxia-induced vascular endothelial injury and inflammatory responses in male mice. Take together, our research has uncovered a new process by which SUMOylation of FADD controls the occurrence of hypoxia-induced necroptosis in endothelial cells, which could identify new therapeu-tic targets for hypoxia-induced diseases.

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Section: Discussionmentioning

confidence: 51%

Hypoxia-mediated SUMOylation of FADD exacerbates endothelial cell injury via the RIPK1-RIPK3-MLKL sig-naling axis

Yu,

Yang,

Wen

et al. 2024

Preprint

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“…CCL2 has been implicated in the EMT process in various cancer cell types, including head and neck squamous cell carcinomas [38], breast carcinoma cells [29], and glioblastoma [39]. We investigated the effect of CCL2 stimulation on EMT progression in drug-sensitive cancer cells.…”

Section: Ccl2 Confers Osimertinib Resistance Through Zeb1 Upregulationmentioning

confidence: 99%

The CCL2-CCR2 axis contributes to acquired osimertinib resistance in lung cancer by upregulating Zeb1 expression

Chang,

Tsai,

et al. 2023

Preprint

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Osimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), effectively treats non-small-cell lung cancer patients with EGFR activation mutations or those with acquired T790M resistance mutation following EGFR-TKIs therapy. However, the development of drug resistance remains a significant clinical challenge. Therefore, we aimed to investigate novel cytokine signaling pathways contributing to osimertinib resistance in lung cancer. Our findings revealed that the CCL2-CCR2 signaling pathway is pivotal in osimertinib resistance development. We observed elevated CCL2 expression in EGFR TKIs-resistant lung cancer cells compared to treatment-naive EGFR mutant cells. Furthermore, ectopic expression of CCL2 in osimertinib-sensitive lung cancer cells conferred resistance to osimertinib in vitro and in vivo. CCL2 knockdown improved osimertinib-induced apoptosis in lung cancer cells. Osimertinib-resistant cells exhibited epithelial-mesenchymal transition phenotypes. We demonstrated that CCL2 primarily confers osimertinib resistance through CCR2, STAT3, and ERK, upregulating Zeb1 expression. Finally, combining a STAT3 inhibitor with osimertinib overcoming resistance in vivo. In conclusion, CCL2 significantly contributes to acquired osimertinib resistance in lung cancer. Targeting the CCL2-CCR2-STAT3/ERK-Zeb1 signaling pathway holds therapeutic potential for overcoming osimertinib resistance and improving treatment outcomes.

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“…It was well established that IL-17, TNF, NF-κB, Toll-like receptor, cell cycle, JAK-STAT, cAMP, ferroptosis, and others are closely related mechanisms of cancer [22][23][24][25][26][27][28][29]. For instance, Jiang et al reported that circKPNB1 was overexpressed in GBM and was correlated with poor survival time.…”

Section: Plos Onementioning

confidence: 99%

Overexpression of TMEM150A in glioblastoma multiforme patients correlated with dismal prognoses and compromised immune statuses

Fan,

Xu,

et al. 2023

PLoS ONE

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Transmembrane proteins have exhibited a significant correlation with glioblastoma multiforme (GBM). The current study elucidates the roles of transmembrane protein 150A (TMEM150A) in GBM. Data on patients with GBM were collected from The Cancer Genome Atlas and Xena databases. The objective was to identify the expression levels of TMEM150A in patients with GBM, and evaluate its diagnostic and prognostic values, accomplished using the receiver operating characteristic and survival analyses. On a cellular level, Cell Counting Kit-8, Wound healing, and Transwell experiments were performed to gauge the impact of TMEM150A on cell growth and migration. The study further investigated the correlation between TMEM150A expression and immune status, along with ribonucleic acid (RNA) modifications in GBM. The findings demonstrated TMEM150A overexpression in the cancerous tissues of patients with GBM, with an area under the curve value of 0.95. TMEM150A overexpression was significantly correlated with poor prognostic indicators. TMEM150A overexpression and isocitrate dehydrogenase (IDH) mutation status were predictive of poor survival time among patients with GBM. In vitro experiments indicated that suppressing TMEM150A expression could inhibit GBM cell proliferation, migration, and invasion. Moreover, TMEM150A overexpression was associated with stromal, immune, and estimate scores, immune cells (such as the T helper (Th) 17 cells, Th2 cells, and regulatory T cells), cell markers, and RNA modifications. Therefore, TMEM150A overexpression might serve as a promising biomarker for predicting poor prognosis in patients with GBM. Inhibiting TMEM150A expression holds the potential for improving the survival time of patients with GBM.

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CCL2-targeted ginkgolic acid exerts anti-glioblastoma effects by inhibiting the JAK3-STAT1/PI3K-AKT signaling pathway

Cited by 7 publications

References 39 publications

Hypoxia-mediated SUMOylation of FADD exacerbates endothelial cell injury via the RIPK1-RIPK3-MLKL sig-naling axis

Hypoxia-mediated SUMOylation of FADD exacerbates endothelial cell injury via the RIPK1-RIPK3-MLKL sig-naling axis

The CCL2-CCR2 axis contributes to acquired osimertinib resistance in lung cancer by upregulating Zeb1 expression

Overexpression of TMEM150A in glioblastoma multiforme patients correlated with dismal prognoses and compromised immune statuses

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