Doxorubicin blocks proliferation of cancer cells through proteolytic activation of CREB3L1

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Published on: January 7, 2019

Bray Denard1, Ching Lee, Jin Ye

  • 1Department of Molecular Genetics , University of Texas Southwestern Medical Center , Dallas , United States.

Elife
|December 21, 2012
PubMed

Insights

Doxorubicin chemotherapy activates ceramide synthesis, leading to CREB3L1 activation. This transcription factor induces cell cycle inhibitors, offering a potential biomarker for doxorubicin sensitivity in cancer treatment.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Doxorubicin is a widely used chemotherapy agent.
  • The precise mechanism of doxorubicin's anti-cancer effects is not fully understood.

Purpose of the Study:

  • To elucidate the molecular mechanism by which doxorubicin inhibits cancer cell proliferation.
  • To investigate the role of ceramide and CREB3L1 in doxorubicin's action.

Main Methods:

  • Studied the effect of doxorubicin on ceramide synthesis and CREB3L1 activation.
  • Utilized gene knockdown and overexpression techniques in human cancer cell lines (Huh7, MCF-7) and fibroblasts (SV589).
  • Analyzed the cleavage of CREB3L1 by Site-1 Protease and Site-2 Protease and its nuclear translocation.

Main Results:

  • Doxorubicin treatment stimulates de novo ceramide synthesis, activating the transcription factor CREB3L1.
  • Activated CREB3L1 translocates to the nucleus, inducing genes like p21 that inhibit cell cycle progression.
  • Knockdown of CREB3L1 conferred doxorubicin resistance, while its overexpression enhanced sensitivity.

Conclusions:

  • Doxorubicin's anti-cancer activity is mediated, in part, by the ceramide-CREB3L1 pathway.
  • CREB3L1 is a key mediator of doxorubicin-induced cell cycle arrest.
  • CREB3L1 expression levels may serve as a predictive biomarker for doxorubicin efficacy in cancer patients.
Keywords:
CREB3L1Humancancerceramidedoxorubicin

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