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Real-Time Monitoring of Aurora kinase A Activation using Conformational FRET Biosensors in Live Cells
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Published on: July 30, 2020

Aurora and IKK kinases cooperatively interact to protect multiple myeloma cells from Apo2L/TRAIL

Laura Mazzera1, Guerino Lombardi, Manuela Abeltino

  • 1Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy;

Blood
|August 27, 2013
PubMed

Insights

Aurora kinases interact with NF-κB pathway regulators to activate nuclear factor-κB (NF-κB) in multiple myeloma (MM), promoting TRAIL resistance. Blocking Aurora kinases sensitizes MM to TRAIL by inhibiting NF-κB activation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Constitutive activation of nuclear factor-κB (NF-κB) pathways is common in multiple myeloma (MM) and contributes to resistance to Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL).
  • Aurora kinases are implicated in cell proliferation and survival, but their role in NF-κB activation and TRAIL resistance in MM is not fully understood.

Purpose of the Study:

  • To investigate the interaction between Aurora kinases and NF-κB pathway regulators in MM.
  • To determine if pharmacological inhibition of Aurora kinases can sensitize MM cells to TRAIL therapy.

Main Methods:

  • Co-immunoprecipitation assays to assess physical interactions between Aurora kinases and IκB kinase (IKK) complexes (IKKα and IKKβ).
  • Western blotting to analyze protein phosphorylation and expression of NF-κB target genes.
  • Cell viability assays to evaluate TRAIL sensitivity in MM cells treated with pan-Aurora kinase inhibitors (pan-AKIs).
  • In vivo studies using a human myeloma xenograft model.

Main Results:

  • Aurora kinases physically and functionally interact with IKKα and IKKβ to activate NF-κB in MM cells.
  • TRAIL treatment increases Aurora and IKK phosphorylation and their interaction, promoting prosurvival signaling.
  • Pan-AKIs disrupt Aurora-IKK interactions, inhibit NF-κB activation, and block TRAIL-induced expression of antiapoptotic genes (A1/Bfl-1, Mcl-1).
  • Combination therapy with pan-AKIs and TRAIL demonstrated significant efficacy in a multidrug-resistant MM xenograft model.

Conclusions:

  • Aurora kinases and IKK kinases cooperate to promote NF-κB activation and TRAIL resistance in multiple myeloma.
  • Pharmacological inhibition of Aurora kinases represents a promising strategy to enhance TRAIL efficacy in MM.
  • Combining Aurora kinase inhibitors with TRAIL may offer a novel therapeutic approach for MM patients, including those with drug-resistant disease.

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