SERPINA1 promotes the invasion, metastasis, and proliferation of pancreatic ductal adenocarcinoma via the PI3K/Akt/NF-κB pathway

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY Biochemical pharmacology Pub Date : 2024-10-18 DOI:10.1016/j.bcp.2024.116580

Chen Xiubing , Li Huazhen , Wei Xueyan , Ning Jing , Li Qing , Jiang Haixing , Qin Shanyu , Lu Jiefu

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Abstract

Serpin peptidase inhibitor clade A member 1 (SERPINA1) is highly expressed in a variety of solid tumors. However, its role in pancreatic ductal adenocarcinoma (PDAC) remains unclear. Here, we report evidence that SERPINA1 acts as a potent oncogene to drive its extremely malignant character. We found that elevated SERPINA1 expression in primary tumors was associated with lymph node metastasis and shorter survival in PDAC patients. Mechanistic investigations revealed that overexpression of SERPINA1 induced nuclear translocation and phosphorylation of the p65 subunit through the PI3K/Akt/NF-κB pathway, thereby promoting the invasion, metastasis and proliferation of PDAC cells in vitro and in vivo. Conversely, the knockdown of SERPINA1 attenuated this signaling pathway and restored the phenotype of PDAC cells overexpressing SERPINA1. Overall, our study reveals that SERPINA1 affects the properties of PDAC through the PI3K/Akt/NF-κB pathway, and its activation confers the clinical features of epithelial-mesenchymal transition and proliferation in the disease.

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SERPINA1通过PI3K/Akt/NF-κB途径促进胰腺导管腺癌的侵袭、转移和增殖。

血清素肽酶抑制剂 A 族成员 1（SERPINA1）在多种实体瘤中高度表达。然而，它在胰腺导管腺癌（PDAC）中的作用仍不清楚。在此，我们报告了 SERPINA1 作为一种强效致癌基因驱动胰腺导管腺癌极度恶性的证据。我们发现，原发性肿瘤中 SERPINA1 表达的升高与淋巴结转移和 PDAC 患者的生存期缩短有关。机理研究发现，SERPINA1 的过表达可通过 PI3K/Akt/NF-κB 通路诱导 p65 亚基的核转位和磷酸化，从而促进 PDAC 细胞在体外和体内的侵袭、转移和增殖。相反，敲除 SERPINA1 可减轻这一信号通路，并恢复过表达 SERPINA1 的 PDAC 细胞的表型。总之，我们的研究揭示了SERPINA1通过PI3K/Akt/NF-κB途径影响PDAC的特性，其激活赋予了该疾病上皮-间质转化和增殖的临床特征。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.