DUSP2 recruits CSNK2A1 to suppress AKT1-mediated apoptosis resistance under hypoxic microenvironment in pancreatic cancer

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 cance...

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Bibliographic Details
Published in:Cancer letters 2023-08, Vol.568, p.216288-216288, Article 216288
Main Authors: Zhang, Yangyang, Kong, Rui, Yang, Wenbo, Hu, Keyi, Zhao, Zhongjie, Li, Le, Geng, Xinglong, Liu, Liwei, Chen, Hongze, Xiao, Peng, Liu, Danxi, Luo, Yan, Chen, Hua, Hu, Jisheng, Sun, Bei
Format: Article
Language:English
Subjects:
AKT1 signal pathway
Apoptosis
Carcinoma, Pancreatic Ductal - pathology
Cell Line, Tumor
Competitive binding
Dual Specificity Phosphatase 2 - metabolism
DUSP2
Humans
Hypoxia
Pancreatic Neoplasms
Pancreatic Neoplasms - pathology
Positive feedback loop
Post-translational modification
Proto-Oncogene Proteins c-akt
Tumor Microenvironment
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Summary: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.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2023.216288