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Published on: February 16, 2015

Transcriptional modulation of apoptosis regulators by roscovitine and related compounds

Xènia Garrofé-Ochoa1, Ana M Cosialls, Judit Ribas

  • 1Molecular Pharmacology Group, Departament de Medicina Experimental, IRBLLEIDA-Universitat de Lleida, C/Montserrat Roig 2, 25008, Lleida, Catalunya, Spain.

Apoptosis : an International Journal on Programmed Cell Death
|April 21, 2011
PubMed

Insights

Cyclin-dependent kinase (CDK) inhibitors like roscovitine induce apoptosis by disrupting transcription. MCL-1 depletion, not PUMA increase, correlates with cell death, suggesting a disrupted MCL-1/NOXA balance is key in roscovitine-induced apoptosis.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Therapeutics

Background:

  • Cyclin-dependent kinase (CDK) inhibitors, such as roscovitine, seliciclib, and olomoucine, are investigated for cancer therapy due to their ability to induce apoptosis.
  • These compounds activate the intrinsic/mitochondrial pathway of apoptosis in proliferating cells.
  • Understanding the transcriptional changes during this process is crucial for therapeutic development.

Purpose of the Study:

  • To characterize the intrinsic apoptosis pathway induced by CDK inhibitors.
  • To investigate the role of PUMA and MCL-1 gene expression in roscovitine-induced apoptosis.
  • To elucidate the mechanism of apoptosis triggered by CDK inhibitors.

Main Methods:

  • Transcriptional analysis using reverse transcriptase-multiplex ligation-dependent probe amplification (RT-MLPA).
  • Treatment of five cell lines with roscovitine.
  • Analysis of PUMA, MCL-1, and NOXA mRNA and protein levels.
  • Assessment of apoptosis induction in p53-proficient and p53-deficient cells.

Main Results:

  • Roscovitine treatment caused a significant reduction in most transcripts, consistent with CDK7 and CDK9 inhibition.
  • PUMA mRNA levels increased in p53-functional neuroblastoma cells but not in p53-deficient cells.
  • MCL-1 mRNA and protein depletion correlated strongly with cell death, while PUMA increase did not.
  • NOXA protein levels decreased less significantly than MCL-1.

Conclusions:

  • Increased PUMA expression is not directly associated with roscovitine-induced apoptosis.
  • Depletion of MCL-1 is a critical factor in roscovitine-mediated cell death.
  • The disruption of the MCL-1/NOXA balance is hypothesized to be a key event in apoptosis induction by CDK inhibitors.

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