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Inhibition of COP9-signalosome (CSN) deneddylating activity and tumor growth of diffuse large B-cell lymphomas by

Mary Pulvino1, Luojing Chen2, David Oleksyn2

  • 1Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, USA.

Oncotarget
|July 6, 2015
PubMed

Insights

The antibiotic doxycycline effectively inhibits diffuse large B-cell lymphoma (DLBCL) growth by targeting the COP-9 signalosome (CSN5) pathway. This finding suggests doxycycline as a potential new therapy for DLBCL and other non-Hodgkin lymphomas.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma.
  • Novel therapeutic agents are needed to improve treatment outcomes for DLBCL.
  • Doxycycline, a common antibiotic, was investigated for anti-lymphoma properties.

Purpose of the Study:

  • To identify small-molecule compounds that inhibit DLBCL cell proliferation and survival.
  • To evaluate doxycycline as a potential therapeutic agent for DLBCL.
  • To elucidate the molecular mechanisms underlying doxycycline's anti-lymphoma effects.

Main Methods:

  • In vitro cell culture assays to assess DLBCL cell growth inhibition.
  • Mouse xenograft models to evaluate efficacy in vivo.
  • Analysis of signaling pathways and protein interactions, including COP-9 signalosome (CSN) and HSP90.
  • Gene knockdown studies (CSN5).

Main Results:

  • Doxycycline significantly inhibits DLBCL cell proliferation and survival both in vitro and in vivo.
  • Doxycycline accumulates in DLBCL cells and modulates key lymphomagenesis pathways.
  • Doxycycline's mechanism involves targeting the deneddylating activity of COP-9 signalosome (CSN), specifically CSN5, impacting the CSN5-HSP90 pathway.
  • Knockdown of CSN5 mimicked doxycycline's effects on DLBCL cell survival and HSP90 function.
  • Doxycycline also inhibited other non-Hodgkin lymphoma cell types in vitro.

Conclusions:

  • Doxycycline demonstrates significant anti-lymphoma activity against DLBCL.
  • The CSN5-HSP90 pathway is a key target of doxycycline in DLBCL cells.
  • Doxycycline shows promise as a potential therapeutic agent for DLBCL and potentially other non-Hodgkin lymphoma subtypes.
Keywords:
COP-9 signalosomeCSN5DLBCLdoxycyclinetherapeutic agent

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