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Activation of ATF4 mediates unwanted Mcl-1 accumulation by proteasome inhibition

Jinsong Hu1, Nana Dang, Eline Menu

  • 1Department of Genetics and Molecular Biology, Medical School of Xi'an Jiaotong University, China.

Blood
|December 1, 2011
PubMed

Insights

Proteasome inhibition in multiple myeloma increases Mcl-1 protein via the unfolded protein response (UPR) and activating transcription factor-4 (ATF4). Targeting ATF4 reduces Mcl-1, enhancing drug sensitivity.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cellular Stress Response

Background:

  • Myeloid cell leukemia-1 (Mcl-1) is a key anti-apoptotic protein crucial for multiple myeloma (MM) cell survival and drug resistance.
  • Proteasome inhibition, a common MM treatment strategy, can paradoxically increase Mcl-1 levels, contributing to bortezomib resistance.
  • The precise mechanisms driving Mcl-1 accumulation under proteasome inhibition remain incompletely understood.

Purpose of the Study:

  • To investigate if the unfolded protein response (UPR) induces Mcl-1 accumulation during proteasome inhibition in MM.
  • To elucidate the role of endoplasmic reticulum (ER) stress in regulating Mcl-1 expression in this context.

Main Methods:

  • Quantitative RT-PCR and Western blot analyses were employed to assess Mcl-1 and activating transcription factor-4 (ATF4) expression.
  • Chromatin immunoprecipitation (ChIP) assays were performed to evaluate ATF4 binding to the Mcl-1 promoter.
  • Gene knockdown of ATF4 was utilized to determine its functional role in Mcl-1 regulation and bortezomib sensitivity.

Main Results:

  • Proteasome inhibition significantly enhanced the translation of ATF4, a key UPR effector, in MM cells.
  • ChIP analysis confirmed that bortezomib treatment promotes ATF4 binding to a specific site on the Mcl-1 promoter.
  • Knockdown of ATF4 attenuated bortezomib-induced Mcl-1 upregulation and markedly sensitized MM cells to bortezomib-induced apoptosis.

Conclusions:

  • The UPR, specifically through its ATF4 pathway, is identified as a critical mechanism responsible for Mcl-1 upregulation induced by proteasome inhibition in multiple myeloma.
  • These findings highlight the ATF4-Mcl-1 axis as a potential therapeutic target to overcome drug resistance in MM.

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