2. Academic Validation
  3. DUSP2 recruits CSNK2A1 to suppress AKT1-mediated apoptosis resistance under hypoxic microenvironment in pancreatic cancer

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

  • Cancer Lett. 2023 Jun 29;568:216288. doi: 10.1016/j.canlet.2023.216288.
Yangyang Zhang 1,  Rui Kong 1,  Wenbo Yang 1,  Keyi Hu 1,  Zhongjie Zhao 1,  Le Li 1,  Xinglong Geng 1,  Liwei Liu 1,  Hongze Chen 1,  Peng Xiao 1,  Danxi Liu 1,  Yan Luo 1,  Hua Chen 1,  Jisheng Hu 2,  Bei Sun 3
Affiliations

Affiliations

  • 1 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.
  • 2 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. Electronic address: hujisheng0816@126.com.
  • 3 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. Electronic address: sunbei70@tom.com.
PMID: 37390887 DOI: 10.1016/j.canlet.2023.216288
Abstract

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.

Keywords

AKT1 signal pathway; Competitive binding; DUSP2; Positive feedback loop; Post-translational modification.

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