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

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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.

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Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

ATCC:

American Type Culture Collection

BCA:

bicinchoninic acid

CCK-8:

Cell Counting Kit-8

ECAR:

extracellular acidification rate

ERK:

extracellular signal-regulated kinase

FBS:

fetal bovine serum

FCCP:

carbonyl cyanide 4-[trifluoromethoxy] phenylhydrazone

GEO:

Gene Expression Omnibus

GSEA:

gene set enrichment analysis

GTEx:

Genotype-Tissue Expression

IHC-P:

immunohistochemical

IL-1:

interleukin-1

IRAKs:

interleukin-1 receptor-associated kinases

JAK:

Janus kinase

MA:

maslinic acid

MyD88:

myeloid differentiation factor 88

NF-κB:

nuclear factor-κB

OCR:

oxygen consumption rate

PDAC:

pancreatic ductal adenocarcinoma

qRT-PCR:

quantitative real-time polymerase chain reaction

RNAi:

RNA interference

R&A:

rotenone and antimycin A

SUV max:

maximum standardized uptake value

TCGA:

The Cancer Genome Atlas

TLR9:

Toll-like receptor 9

TME:

tumor microenvironment

TRAF6:

tumor necrosis factor receptor associated factor 6

WB:

Western blotting

2-DG:

2-deoxy-D-glucose

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Funding

This work was supported by the National Natural Science Foundation of China (grant number 81874175 to Y.W.S.; 81902377 to D.J.L.; 81702844 to Y.M.H.; 81702726 to W.L.).

Author information

Author notes

  1. Jian Yang, De-Jun Liu, Jia-Hao Zheng and Rui-Zhe He contributed equally.

Authors and Affiliations

  1. Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    Jian Yang, De-Jun Liu, Jia-Hao Zheng, Rui-Zhe He, Da-Peng Xu, Min-Wei Yang, Hong-Fei Yao, Xue-Liang Fu, Jian-Yu Yang, Yan-Miao Huo, Ling-Ye Tao, Rong Hua, Yong-Wei Sun & Wei Liu

  2. Central Laboratory, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China

    De-Jun Liu & Xian-Ming Kong

  3. Shanghai University of Medicine & Health Sciences, Shanghai, 201318, China

    De-Jun Liu & Xian-Ming Kong

  4. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

    Shu-Heng Jiang

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Contributions

S.H.J. and W.L. designed the study and reviewed the manuscript. J.Y., D.J.L. and J.H.Z. performed the in vitro and in vivo experiments and wrote the manuscript. R.Z.H. and D.P.X. conducted the bioinformatics analyses. W.L., X.M.K. and Y.W.S. were involved in the conceptualization, supervision, project administration and funding acquisition. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Yong-Wei Sun, Xian-Ming Kong, Shu-Heng Jiang or Wei Liu.

Ethics declarations

Ethics approval and consent to participate

The clinical sample study was approved under number RA-2019-116 assigned by the Research Ethics Committee of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University. All manipulations in the animal study were performed under approved protocol number 20141204 assigned by the Research Ethics Committee of East China Normal University. The mouse studies were undertaken in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Yang, J., Liu, DJ., Zheng, JH. et al. IRAK2-NF-κB signaling promotes glycolysis-dependent tumor growth in pancreatic cancer. Cell Oncol. 45, 367–379 (2022). https://doi.org/10.1007/s13402-022-00670-z

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