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MAP4K4 promotes pancreatic tumorigenesis via phosphorylation and activation of mixed lineage kinase 3

Sunil Kumar Singh1, Sandeep Kumar1, Navin Viswakarma1

  • 1Department of Surgery, Division of Surgical Oncology, the University of Illinois at Chicago, Chicago, IL, 60612, USA.

Oncogene
|September 13, 2021
PubMed

Insights

The study reveals that MAP4K4 promotes pancreatic cancer by phosphorylating MLK3, enhancing cancer cell growth and migration. Targeting MAP4K4 with GNE-495 effectively reduced tumor burden and improved survival in preclinical models.

Area of Science:

  • Molecular oncology
  • Signal transduction pathways
  • Cancer biology

Background:

  • Mitogen-activated protein kinase kinase kinase 4 (MAP4K4) is implicated in various pathologies, including cancer.
  • The precise mechanisms by which MAP4K4 drives pancreatic cancer progression remain incompletely elucidated.
  • MAP4K4's role in cancer may involve organ-specific downstream targets.

Purpose of the Study:

  • To identify and characterize the direct downstream targets of MAP4K4 in pancreatic cancer.
  • To investigate the functional consequences of MAP4K4-MLK3 interaction in pancreatic cancer.
  • To evaluate the therapeutic potential of targeting MAP4K4 in pancreatic cancer models.

Main Methods:

  • Co-immunoprecipitation assays to confirm MAP4K4-MLK3 association.
  • In vitro kinase assays and Western blotting to assess MLK3 phosphorylation and activity.
  • Cell proliferation, migration, and colony formation assays.
  • In vivo studies using KPC mouse models of pancreatic cancer.
  • Pharmacological inhibition of MAP4K4 using GNE-495.

Main Results:

  • Mixed lineage kinase 3 (MLK3) was identified as a direct downstream target of MAP4K4.
  • MAP4K4 phosphorylates MLK3 at Thr738, enhancing its kinase activity and downstream signaling.
  • MAP4K4-mediated MLK3 phosphorylation promotes pancreatic cancer cell proliferation, migration, and colony formation.
  • MAP4K4 is overexpressed in human pancreatic tumors and correlates with disease progression.
  • Pharmacological inhibition of MAP4K4 with GNE-495 suppressed pancreatic cancer cell growth, migration, induced cell death, and cell cycle arrest.
  • GNE-495 treatment reduced tumor burden, extended survival in KPC mice, decreased tumor stroma, and induced cell death in murine tumors.

Conclusions:

  • MAP4K4-driven MLK3 phosphorylation is a key mechanism promoting pancreatic cancer progression.
  • Targeting MAP4K4 with pharmacological inhibitors like GNE-495 shows significant therapeutic potential for pancreatic cancer.
  • Inhibition of MAP4K4 may represent a viable strategy to alleviate pancreatic cancer tumor burden and improve patient outcomes.

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