1. Academic Validation
  2. IRAK2-NF-κB signaling promotes glycolysis-dependent tumor growth in pancreatic cancer

IRAK2-NF-κB signaling promotes glycolysis-dependent tumor growth in pancreatic cancer

  • Cell Oncol (Dordr). 2022 Jun;45(3):367-379. doi: 10.1007/s13402-022-00670-z.
Jian Yang  # 1 De-Jun Liu  # 1 2 3 Jia-Hao Zheng  # 1 Rui-Zhe He  # 1 Da-Peng Xu 1 Min-Wei Yang 1 Hong-Fei Yao 1 Xue-Liang Fu 1 Jian-Yu Yang 1 Yan-Miao Huo 1 Ling-Ye Tao 1 Rong Hua 1 Yong-Wei Sun 4 Xian-Ming Kong 5 6 Shu-Heng Jiang 7 Wei Liu 8
Affiliations

Affiliations

  • 1 Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 2 Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
  • 3 Shanghai University of Medicine & Health Sciences, Shanghai, 201318, China.
  • 4 Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. syw0616@126.com.
  • 5 Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. kxm666@aliyun.com.
  • 6 Shanghai University of Medicine & Health Sciences, Shanghai, 201318, China. kxm666@aliyun.com.
  • 7 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. shjiang@shsci.org.
  • 8 Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China. sugliuwei2004@126.com.
  • # Contributed equally.
Abstract

Background: Metabolic reprogramming has emerged as a core hallmark of Cancer, and Cancer metabolism has long been equated with aerobic glycolysis. Moreover, hypoxia and the hypovascular tumor microenvironment (TME) are major hallmarks of pancreatic ductal adenocarcinoma (PDAC), in which glycolysis is imperative for tumor cell survival and proliferation. Here, we explored the impact of interleukin 1 receptor-associated kinase 2 (IRAK2) on the biological behavior of PDAC and investigated the underlying mechanism.

Methods: The expression pattern and clinical relevance of IRAK2 was determined in GEO, TCGA and Ren Ji datasets. Loss-of-function and gain-of-function studies were employed to investigate the cellular functions of IRAK2 in vitro and in vivo. Gene set enrichment analysis, Seahorse metabolic analysis, immunohistochemistry and Western blot were applied to reveal the underlying molecular mechanisms.

Results: We found that IRAK2 is highly expressed in PDAC patient samples and is related to a poor prognosis. IRAK2 knockdown led to a significant impairment of PDAC cell proliferation via an aberrant Warburg effect. Opposite results were obtained after exogenous IRAK2 overexpression. Mechanistically, we found that IRAK2 is critical for sustaining the activation of transcription factors such as those of the nuclear factor-κB (NF-κB) family, which have increasingly been recognized as crucial players in many steps of Cancer initiation and progression. Treatment with maslinic acid (MA), a NF-κB Inhibitor, markedly attenuated the aberrant oncological behavior of PDAC cells caused by IRAK2 overexpression.

Conclusions: Our data reveal a role of IRAK2 in PDAC metabolic reprogramming. In addition, we obtained novel insights into how immune-related pathways affect PDAC progression and suggest that targeting IRAK2 may serve as a novel therapeutic approach for PDAC.

Keywords

Aerobic glycolysis; Glycolytic metabolism; Interleukin receptor-associated kinase 2; NF-kappaB axis; Pancreatic ductal adenocarcinoma.

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