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核 MAST4 通过与 AKT3 相互作用抑制 FOXO3 并诱导胰腺导管腺癌的化疗耐药性。

Nuclear MAST4 Suppresses FOXO3 through Interaction with AKT3 and Induces Chemoresistance in Pancreatic Ductal Carcinoma.

机构信息

Department of Molecular Pathology, Nara Medical University, 840 Shijo-cho, Kashihara 634-8521, Nara, Japan.

Research Institute of Oral Science, Nihon University School of Dentistry at Matsudo, Matsudo 271-8587, Chiba, Japan.

出版信息

Int J Mol Sci. 2024 Apr 5;25(7):4056. doi: 10.3390/ijms25074056.

DOI:10.3390/ijms25074056
PMID:38612866
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11012408/
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is highly malignant, with a 5-year survival rate of less than 10%. Furthermore, the acquisition of anticancer drug resistance makes PDAC treatment difficult. We established MIA-GEM cells, a PDAC cell line resistant to gemcitabine (GEM), a first-line anticancer drug, using the human PDAC cell line-MIA-PaCa-2. Microtubule-associated serine/threonine kinase-4 () expression was increased in MIA-GEM cells compared with the parent cell line. Through inhibitor screening, dysregulated AKT signaling was identified in MIA-GEM cells with overexpression of AKT3. knockdown effectively suppressed AKT3 overexpression, and both and AKT3 translocation into the nucleus, phosphorylating forkhead box O3a (FOXO3) in MIA-GEM cells. Modulating FOXO3 target gene expression in these cells inhibited apoptosis while promoting stemness and proliferation. Notably, nuclear demonstrated higher expression in GEM-resistant PDAC cases compared with that in the GEM-sensitive cases. Elevated expression correlated with a poorer prognosis in PDAC. Consequently, nuclear emerges as a potential marker for GEM resistance and poor prognosis, representing a novel therapeutic target for PDAC.

摘要

胰腺导管腺癌 (PDAC) 恶性程度高，5 年生存率低于 10%。此外，获得抗癌药物耐药性使得 PDAC 的治疗变得困难。我们使用人胰腺导管腺癌细胞系-MIA-PaCa-2 建立了对吉西他滨 (GEM) 耐药的 PDAC 细胞系 MIA-GEM。与亲本细胞系相比，MIA-GEM 细胞中微管相关丝氨酸/苏氨酸激酶-4 () 的表达增加。通过抑制剂筛选，我们发现 AKT3 过表达的 MIA-GEM 细胞中 AKT 信号通路失调。抑制表达可有效抑制 AKT3 过表达，以及 和 AKT3 向核内易位，磷酸化叉头框蛋白 O3a (FOXO3) 在 MIA-GEM 细胞中。调节这些细胞中 FOXO3 靶基因的表达可抑制细胞凋亡，同时促进干性和增殖。值得注意的是，与 GEM 敏感病例相比，GEM 耐药 PDAC 病例中的核 表达更高。升高的 表达与 PDAC 的预后不良相关。因此，核 可作为 GEM 耐药和预后不良的潜在标志物，代表 PDAC 的一个新的治疗靶点。

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