文章：

敲除p21激活激酶4通过非自噬途径刺激胰腺癌细胞MHC I表达

Knockout of p21-Activated Kinase 4 Stimulates MHC I Expression of Pancreatic Cancer Cells via an Autophagy-Independent Pathway

原文发布日期：3 February 2025

DOI: 10.3390/cancers17030511

类型: Article

开放获取: 是

英文摘要：

Background/Objectives: Pancreatic ductal adenocarcinoma (PDA) is one of the most malignant solid cancers. KRAS mutation accounts for over 90% of cases. p21-activated kinases (PAKs) act downstream of KRAS and are involved in tumorigenesis. The inhibition of PAK4 suppresses PDA by stimulating the tumor infiltration of cytotoxic T cells. The major histocompatibility complex class I (MHC I) is a key in presenting antigens to cytotoxic T cells. MHC I degradation via autophagy promotes the immune evasion of pancreatic cancer. We investigated the effect of PAK4 inhibition on MHC I expression and autophagy. Methods: In this study, using proteomic analysis, fluorescence-activated cell sorting (FACS), and immunoblotting, we examined the effect of PAK4 knockout (KO) in human PDA cells on the expression of MHC I and autophagy to identify the mechanism involved in the stimulation of cytotoxic T cells by PAK4 inhibition. Results: We found that PAK4 KO increased MHC I expression in two human PDA cell lines: MiaPaCa-2 and PANC-1. PAK4 KO also increased cancer cell autophagy. However, the inhibition of autophagy by chloroquine (CQ) did not affect the effect of PAK4 KO on apoptosis and cell death. More importantly, the inhibition of autophagy by CQ did not alter the expression of MHC I stimulated by PAK4 KO, indicating that PAK4 KO stimulated MHC I expression via an autophagy-independent pathway. Conclusions: We identified a role of PAK4 in MHC I expression by PDA cells, which is independent of autophagy.

摘要翻译： 

背景/目的：胰腺导管腺癌（PDA）是恶性程度最高的实体肿瘤之一，其中超过90%的病例存在KRAS突变。p21激活激酶（PAKs）作为KRAS下游信号分子参与肿瘤发生。抑制PAK4可通过促进细胞毒性T细胞向肿瘤浸润来抑制PDA进展。主要组织相容性复合体I类分子（MHC I）是向细胞毒性T细胞呈递抗原的关键分子。通过自噬途径降解MHC I可促进胰腺癌的免疫逃逸。本研究旨在探讨PAK4抑制对MHC I表达及自噬的影响。方法：本研究通过蛋白质组学分析、流式细胞分选技术和免疫印迹实验，检测人源PDA细胞中PAK4基因敲除（KO）对MHC I表达及自噬的影响，以阐明PAK4抑制促进细胞毒性T细胞活化的作用机制。结果：研究发现，在MiaPaCa-2和PANC-1两种人源PDA细胞系中，PAK4 KO可显著提升MHC I表达水平，同时增强癌细胞自噬活性。然而，氯喹（CQ）介导的自噬抑制并未影响PAK4 KO诱导的细胞凋亡和死亡。更重要的是，CQ抑制自噬并未改变PAK4 KO对MHC I表达的促进作用，表明PAK4 KO通过不依赖自噬的途径调控MHC I表达。结论：本研究首次揭示PAK4在PDA细胞MHC I表达调控中的作用，该作用机制独立于自噬途径。

原文链接：

Knockout of p21-Activated Kinase 4 Stimulates MHC I Expression of Pancreatic Cancer Cells via an Autophagy-Independent Pathway