Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China; Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
Cancer Lett. 2023 Aug 1;568:216288. doi: 10.1016/j.canlet.2023.216288. Epub 2023 Jun 29.
Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic tumor microenvironment (TME), which aids tumor progression, drug resistance, and immune evasion. Dual-specificity phosphatase 2 (DUSP2), a member of the mitogen-activated protein kinase phosphatase family, regulates pancreatic cancer metastasis. However, its role in the hypoxic TME in PDAC remains unknown. We explored the role of DUSP2 by simulating the hypoxic TME. DUSP2 significantly promoted apoptosis in PDAC both in vitro and in vivo, mainly through AKT1 rather than ERK1/2. Mechanistically, DUSP2 competed with AKT1 to bind to casein kinase 2 alpha 1 (CSNK2A1) and inhibited the phosphorylation of AKT1, which plays a crucial role in apoptosis resistance. Interestingly, aberrant activation of AKT1 resulted in an increase in the ubiquitin E3 ligase tripartite motif-containing 21 (TRIM21), which binds to and mediates the ubiquitination-dependent proteasomal degradation of DUSP2. Overall, we identified CSNK2A1 as a novel binding partner of DUSP2 that promotes PDAC apoptosis through CSN2KA1/AKT1 in an ERK1/2-independent manner. Activation of AKT1 also mediated proteasomal degradation of DUSP2 via the AKT1/TRIM21 positive feedback loop. We propose increasing the level of DUSP2 as a potential therapeutic strategy for PDAC.
胰腺导管腺癌（PDAC）的特征是缺氧肿瘤微环境（TME），这有助于肿瘤的进展、耐药性和免疫逃逸。双特异性磷酸酶 2（DUSP2）是丝裂原活化蛋白激酶磷酸酶家族的成员，调节胰腺癌的转移。然而，其在 PDAC 缺氧 TME 中的作用尚不清楚。我们通过模拟缺氧 TME 来探索 DUSP2 的作用。DUSP2 显著促进了 PDAC 在体外和体内的细胞凋亡，主要是通过 AKT1 而不是 ERK1/2。从机制上讲，DUSP2 与 AKT1 竞争结合酪蛋白激酶 2α1（CSNK2A1）并抑制 AKT1 的磷酸化，这在细胞凋亡抵抗中起着至关重要的作用。有趣的是，AKT1 的异常激活导致泛素 E3 连接酶三部分基序（TRIM）21 的增加，TRIM21 与 DUSP2 结合并介导其依赖泛素的蛋白酶体降解。总的来说，我们确定 CSNK2A1 是 DUSP2 的一种新型结合伙伴，通过 ERK1/2 独立的 CSN2KA1/AKT1 促进 PDAC 细胞凋亡。AKT1 的激活还通过 AKT1/TRIM21 正反馈环介导 DUSP2 的蛋白酶体降解。我们提出增加 DUSP2 的水平作为 PDAC 的一种潜在治疗策略。
