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Induction of endogenous Bcl-xS through the control of Bcl-x pre-mRNA splicing by antisense oligonucleotides

J K Taylor1, Q Q Zhang, J R Wyatt

  • 1Department of Pharmacology, Isis Pharmaceuticals, Carlsbad, CA 92008, USA.

Nature Biotechnology
|November 5, 1999
PubMed

Insights

This study shows that altering the ratio of Bcl-xL to Bcl-xS proteins using antisense oligonucleotides can sensitize cancer cells to apoptosis. This approach offers a new strategy for enhancing chemotherapy and radiation treatment effectiveness.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Biochemistry

Background:

  • Apoptosis resistance is a key challenge in chemotherapy for tumors.
  • The balance of antiapoptotic (e.g., Bcl-xL) and proapoptotic (e.g., Bcl-xS) proteins regulates apoptosis.
  • Alternative splicing of the bcl-x gene produces these antagonistic proteins.

Purpose of the Study:

  • To investigate if manipulating the Bcl-xL/Bcl-xS ratio can sensitize cells to apoptosis.
  • To demonstrate the efficacy of antisense oligonucleotides in altering splice site selection for therapeutic potential.

Main Methods:

  • Utilized antisense oligonucleotides to target and modify the alternative splicing of the bcl-x gene.
  • Exposed treated cells to ultraviolet B radiation and chemotherapeutic drugs.
  • Assessed cellular sensitivity to apoptosis.

Main Results:

  • Altering the Bcl-xL to Bcl-xS ratio via antisense oligonucleotides sensitized cells to apoptosis.
  • This sensitization was observed in response to both ultraviolet B radiation and chemotherapy.
  • Demonstrated successful modification of splice site selection for an endogenous gene.

Conclusions:

  • Antisense oligonucleotides can effectively modulate the Bcl-xL/Bcl-xS ratio, impacting cell survival.
  • This strategy represents a powerful tool for regulating apoptosis and potentially overcoming chemotherapy resistance.
  • The findings highlight a novel therapeutic approach for enhancing cancer treatment outcomes.

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