ArfGAP with the SH3 Domain, Ankyrin Repeat and PH Domain 1 Inversely Regulates Programmed Death-Ligand 1 Through Negative Feedback of Phosphorylated Epithelial Growth Factor Receptor and Activation of Nuclear Factor-Kappa B in Non-Small Cell Lung Cancer.

IF 2.5 4区医学 Q3 ONCOLOGY

Cancer Management and Research Pub Date : 2025-01-20 eCollection Date: 2025-01-01 DOI:10.2147/CMAR.S493368

Naohisa Chiba, Toshi Menju, Yumeta Shimazu, Toshiya Toyazaki, Ryota Sumitomo, Hideaki Miyamoto, Shigeyuki Tamari, Shigeto Nishikawa, Hiroshi Date

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引用次数: 0

Abstract

Background: Signaling pathways centered on the G-protein ADP-ribosylation factor 6 (Arf6) and its downstream effector ArfGAP with the SH3 Domain, Ankyrin Repeat and PH Domain 1 (AMAP1) drive cancer invasion, metastasis, and therapy resistance. The Arf6-AMAP1 pathway has been reported to promote receptor recycling leading to programmed cell death-ligand 1 (PD-L1) overexpression in pancreatic ductal carcinoma. Moreover, AMAP1 regulates of nuclear factor-kappa B (NF-κB), which is an important molecule in inflammation and immune activation, including tumor immune interaction through PD-L1 regulation. In this study, we investigated the function of AMAP1 on PD-L1 expression using lung cancer cells.

Methods: We used two non-small cell lung cancer cell lines. Protein expression was evaluated by Western blotting. AMAP1 and NF-kB expression were reduced by conventional siRNA methods, and osimertinib was used as an epithelial growth factor receptor (EGFR) inhibitor. Multiple analysis of receptor tyrosine kinases (RTKs) was conducted using a semi-comprehensive RTKs assay.

Results: We found that AMAP1 inversely regulated PD-L1 expression. Based on these results, we examined the activation levels of RTKs associated with both AMAP1 and PD-L1. Following a semi-comprehensive phosphorylated RTK assay, we observed the upregulation of phosphorylated EGFR (pEGFR) led by the downregulation of AMAP1. The inhibition of pEGFR by osimertinib downregulates PD-L1 expression. We investigated the relationships between AMAP1, NF-κB, and PD-L1 expression. AMAP1 knockdown upregulated the expression of both NF-κB and PD-L1. Subsequently, NF-κB knockdown downregulated PD-L1 levels, while double knockdown of AMAP1 and NF-κB, restored PD-L1 expression.

Conclusion: AMAP1 may inversely regulate PD-L1 through negative feedback of pEGFR and activation of NF-κB in NSCLC cell lines.

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在非小细胞肺癌中，具有SH3结构域、锚定蛋白重复序列和PH结构域1的ArfGAP通过磷酸化上皮生长因子受体的负反馈和核因子κ B的激活，反向调控程序性死亡配体1。

背景：以g蛋白adp -核基化因子6 （Arf6）及其下游效应因子ArfGAP（具有SH3结构域、锚定蛋白重复序列和PH结构域1 (AMAP1)）为中心的信号通路驱动肿瘤的侵袭、转移和耐药。据报道，Arf6-AMAP1通路可促进受体循环，导致胰腺导管癌中程序性细胞死亡配体1 （PD-L1）过表达。此外，AMAP1调节核因子κB (NF-κB)， NF-κB是炎症和免疫激活的重要分子，包括通过PD-L1调节的肿瘤免疫相互作用。在本研究中，我们利用肺癌细胞研究了AMAP1对PD-L1表达的作用。方法：采用两种非小细胞肺癌细胞系。Western blotting检测蛋白表达。AMAP1和NF-kB的表达通过传统的siRNA方法降低，并用奥西替尼作为上皮生长因子受体（EGFR）抑制剂。受体酪氨酸激酶（RTKs）的多重分析采用半综合RTKs试验进行。结果：我们发现AMAP1负向调控PD-L1的表达。基于这些结果，我们检测了与AMAP1和PD-L1相关的rtk的激活水平。通过半全面的RTK磷酸化实验，我们观察到磷酸化EGFR （pEGFR）的上调是由AMAP1的下调引起的。奥西替尼抑制pEGFR可下调PD-L1的表达。我们研究了AMAP1、NF-κB和PD-L1表达之间的关系。AMAP1敲低可上调NF-κB和PD-L1的表达。随后，NF-κB下调PD-L1水平，而AMAP1和NF-κB的双重下调则恢复PD-L1的表达。结论：AMAP1可能通过负反馈pEGFR和激活NF-κB在非小细胞肺癌细胞系中负调控PD-L1。

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来源期刊

Cancer Management and Research Medicine-Oncology

CiteScore

7.40

自引率

0.00%

发文量

448

审稿时长

16 weeks

期刊介绍： Cancer Management and Research is an international, peer reviewed, open access journal focusing on cancer research and the optimal use of preventative and integrated treatment interventions to achieve improved outcomes, enhanced survival, and quality of life for cancer patients. Specific topics covered in the journal include: ◦Epidemiology, detection and screening ◦Cellular research and biomarkers ◦Identification of biotargets and agents with novel mechanisms of action ◦Optimal clinical use of existing anticancer agents, including combination therapies ◦Radiation and surgery ◦Palliative care ◦Patient adherence, quality of life, satisfaction The journal welcomes submitted papers covering original research, basic science, clinical & epidemiological studies, reviews & evaluations, guidelines, expert opinion and commentary, and case series that shed novel insights on a disease or disease subtype.