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A Novel Function of Molecular Chaperone HSP70: SUPPRESSION OF ONCOGENIC FOXM1 AFTER PROTEOTOXIC STRESS

Marianna Halasi1, Renáta Váraljai2, Elizaveta Benevolenskaya2

  • 1From the Departments of Medicine and.

The Journal of Biological Chemistry
|November 13, 2015
PubMed

Insights

Proteasome inhibitors suppress the oncogenic FOXM1 protein by inducing heat shock protein 70 (HSP70). This novel mechanism reveals HSP70 as a key player in targeting FOXM1 for cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The transcription factor FOXM1 is frequently overexpressed in human cancers, making it a promising target for anticancer therapies.
  • Proteasome inhibitors were previously identified as the first class of drugs capable of targeting FOXM1 in cancer cells.

Purpose of the Study:

  • To elucidate the molecular mechanisms by which proteasome inhibitors suppress FOXM1.
  • To investigate the role of heat shock proteins (HSPs) in FOXM1 regulation under proteotoxic stress.

Main Methods:

  • Treatment of cancer cells with proteasome inhibitors, HSP90 inhibitor PF-4942847, and heat shock.
  • Analysis of FOXM1 and HSP70 expression levels and interactions.
  • Assessment of HSP70 binding to FOXM1 and its effect on FOXM1 DNA-binding ability and transcriptional activity.
  • Evaluation of cancer cell sensitivity to apoptosis induction.

Main Results:

  • Both proteasome inhibitors and HSP90 inhibition/heat shock lead to the induction of the molecular chaperone HSP70.
  • HSP70 binds to FOXM1 following proteotoxic stress, inhibiting its DNA-binding ability and transcriptional autoregulation.
  • This inhibition results in decreased FOXM1 protein expression.
  • Suppression of HSP70 leads to increased FOXM1 expression, while simultaneous inhibition of FOXM1 and HSP70 enhances cancer cell sensitivity to apoptosis.

Conclusions:

  • A novel mechanism for FOXM1 suppression by proteasome inhibitors involves the induction of HSP70.
  • HSP70 directly inhibits FOXM1 activity and protein levels, offering a new therapeutic strategy.
  • Targeting both FOXM1 and HSP70 may enhance the efficacy of anticancer drugs by increasing apoptosis.
Keywords:
70-kD heat shock protein (Hsp70)FOXM1anticancer drugcell deathgene expressionprotein-protein interaction

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