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Evaluation of Substrate Ubiquitylation by E3 Ubiquitin-ligase in Mammalian Cell Lysates
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MAF protein mediates innate resistance to proteasome inhibition therapy in multiple myeloma

Ya-Wei Qiang1, Shiqiao Ye1, Yu Chen1

  • 1Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR.

Blood
|October 30, 2016
PubMed

Insights

Multiple myeloma patients with t(14;16) translocation show resistance to proteasome inhibitor therapy. MAF protein overexpression, stabilized by proteasome inhibitors, drives this resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Multiple myeloma (MM) with t(14;16) translocation has a poor prognosis.
  • This subgroup shows resistance to bortezomib (Bzb), unlike other MM molecular subgroups.
  • The mechanism of innate resistance to proteasome inhibitors (PIs) in MM is unknown.

Purpose of the Study:

  • Investigate how MAF overexpression impacts resistance to proteasome inhibitor (PI) therapy.
  • Determine the role of MAF and GSK3 in PI resistance in t(14;16) MM.
  • Identify novel mechanisms of MAF regulation by PIs.

Main Methods:

  • Quantified MAF protein levels in MM cell lines across different molecular subgroups.
  • Assessed PI sensitivity (IC50 values) in relation to MAF expression.
  • Utilized loss-of-function and gain-of-function models to study MAF's role in PI resistance and apoptosis.
  • Investigated the effect of PI exposure on MAF protein stability and GSK3β-mediated degradation.

Main Results:

  • High MAF protein levels were observed in t(14;16) MM cell lines, correlating with higher PI resistance.
  • Proteasome inhibitor exposure increased MAF protein stability by inhibiting GSK3β-mediated degradation.
  • Silencing MAF sensitized cells to PIs, enhanced apoptosis, and activated caspases.
  • MAF overexpression conferred PI resistance and reduced apoptosis.

Conclusions:

  • MAF overexpression and its stabilization by PIs are key mechanisms of resistance in t(14;16) multiple myeloma.
  • GSK3β plays a critical role in regulating MAF protein stability and subsequent PI resistance.
  • Targeting MAF or its regulatory pathways may overcome PI resistance in this MM subgroup.

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