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Therapeutic potential of targeting IRES-dependent c-myc translation in multiple myeloma cells during ER stress

Y Shi1, Y Yang1, B Hoang1

  • 1Division of Hematology-Oncology, UCLA-Greater Los Angeles VA Healthcare Center and Jonsson Comprehensive Cancer Center, VA West LA Hospital/Hematology-Oncology, W111H, West LA VA Hospital, Los Angeles, CA, USA.

Oncogene
|May 12, 2015
PubMed

Insights

Endoplasmic reticulum stress in multiple myeloma cells maintains c-myc translation via upregulated internal ribosome entry site (IRES) activity. Targeting this pathway with specific compounds synergizes with bortezomib, offering a novel therapeutic strategy.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cellular Stress Response

Background:

  • Protein translation is typically inhibited by the unfolded protein response (UPR) during endoplasmic reticulum (ER) stress.
  • Multiple myeloma (MM) cells exhibit diminished mTORC1 activity under ER stress, yet maintain c-myc protein levels.
  • The mechanism for maintaining c-myc translation during ER stress in MM cells remains unclear.

Purpose of the Study:

  • To investigate the mechanism by which c-myc translation is maintained in ER-stressed multiple myeloma (MM) cells.
  • To explore the role of myc internal ribosome entry site (IRES) function in this process.
  • To identify potential therapeutic targets for MM by modulating c-myc IRES activity.

Main Methods:

  • Assessed myc IRES activity in MM cells under various ER stress conditions (thapsigargin, tunicamycin, bortezomib).
  • Investigated the involvement of MAPK and MNK1 signaling pathways in regulating IRES activity.
  • Utilized a screening approach to identify IRES-binding trans-acting factors, including hnRNP A1 (A1) and RPS25.
  • Developed and tested a compound targeting A1 binding to the myc IRES.

Main Results:

  • Myc IRES activity was significantly upregulated in MM cells experiencing ER stress.
  • MAPK and MNK1 signaling pathways were found to be critical for ER stress-induced IRES activation.
  • hnRNP A1 (A1) and RPS25 were identified as essential IRES-binding factors, with A1 association dependent on MNK1.
  • A specific inhibitor compound blocked A1-myc IRES binding and activity without affecting basal myc translation.
  • Combination therapy of the inhibitor with ER stress inducers, particularly bortezomib, resulted in synergistic cytotoxicity.

Conclusions:

  • Myc IRES activity is a key mechanism for maintaining c-myc translation during ER stress in MM cells.
  • The A1-RPS25 complex, regulated by MNK1, is crucial for ER stress-mediated myc IRES function.
  • Targeting A1-mediated myc IRES activity presents a promising synergistic therapeutic strategy for multiple myeloma, especially in combination with bortezomib.

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