MK2 Promotes the Development and Progression of Pancreatic Neuroendocrine Tumors Mediated by Macrophages and Metabolomic Factors

Damian Jacenik, Eric J. Lebish, Ellen J. Beswick

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Cases of pancreatic neuroendocrine tumors (PNETs) are growing in number, and new treatment options are needed in order to improve patient outcomes. The mitogen-activated protein kinase-activated protein kinase 2 (MK2) is a crucial regulator of cytokine/chemokine production. The significance of MK2 expression and signaling pathway mediated by MK2 in PNETs has not been investigated. To characterize the impact of MK2 on PNET growth, we used the RipTag2 transgenic murine model of PNETs, and we developed a primary PNET cell line for both in vitro and in vivo studies. In the transgenic murine model of PNETs, we found that MK2 inhibition improves survival of mice and prevents PNET progression. MK2 blockade abolished cytokine/chemokine production, which was related to macrophage function. A role for MK2 in the regulation of metabolic factor secretion in PNETs was identified, making this the first study to identify a potential role for the MK2 pathway in regulation of tumor metabolism. Moreover, using an in vitro approach and allograft model of PNETs, we were able to show that macrophages with MK2 depletion exhibit increased cytotoxicity against PNET cells and substantially decreased production of pro-inflammatory cytokines and chemokines, as well as metabolic factors. Taken together, our work identifies MK2 as a potent driver of immune response and metabolic effectors in PNETs, suggesting it is a potential therapeutic target for patients with PNETs.

Original languageEnglish
Article number13561
JournalInternational Journal of Molecular Sciences
Volume23
Issue number21
DOIs
StatePublished - Nov 2022

Bibliographical note

Publisher Copyright:
© 2022 by the authors.

Keywords

  • MAPKAPK2
  • MK2
  • mitogen-activated protein kinase-activated protein kinase 2
  • neuroendocrine tumor
  • pancreas
  • pancreatic neuroendocrine tumor

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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