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Increased expression of the androgen receptor with p300 and interleukin-6 coactivators compensate for oligonucleotide

Marvin Rubenstein1, Courtney M P Hollowell, Patrick Guinan

  • 1Departments of Biochemistry and Urology, Rush University Medical Center, Chicago, IL; Division of Urology, Stroger Hospital of Cook County, Chicago, IL; Chairman-Division of Cellular Biology, Hektoen Institute for Medical Research, 2240 West Ogden Avenue, 2nd floor, Chicago, IL 60612, USA.

Therapeutic Advances in Urology
|April 5, 2013
PubMed
Abstract

Insights

Antisense oligonucleotides targeting bcl-2 in prostate cancer cells led to compensatory increases in androgen receptor (AR) and coactivators. This suggests a potential for tumor transformation to a more aggressive, hormone-insensitive phenotype.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gene Regulation

Background:

  • Antisense oligonucleotides (oligos) are investigated for prostate cancer therapy, targeting proteins like bcl-2.
  • Previous studies showed oligos suppressing bcl-2 induced compensatory changes in apoptosis and androgen receptor (AR) expression in LNCaP cells.
  • These changes suggested increased androgen sensitivity.

Purpose of the Study:

  • To investigate the impact of antisense oligonucleotide treatment against bcl-2 on AR coactivators and cytokines in prostate cancer cells.
  • To understand the adaptive mechanisms of LNCaP cells following bcl-2 suppression.

Main Methods:

  • Evaluation of AR coactivators p300 and CREB binding protein (CREBBP).
  • Assessment of cytokine expression, specifically interleukin (IL)-4 and IL-6.
  • Analysis of gene expression patterns in LNCaP cells treated with antisense oligos targeting bcl-2.

Main Results:

  • Antisense oligo treatment resulted in enhanced expression of p300 and IL-6.
  • LNCaP cells, initially hormone-sensitive with minimal p300 activity, showed increased p300 expression post-treatment.
  • The observed gene expression pattern mimicked that of later-stage, androgen-insensitive prostate cancer.

Conclusions:

  • Antisense oligo treatment against bcl-2 can be evaded by prostate cancer cells through compensatory upregulation of AR and coactivators.
  • These adaptive changes promote tumor growth and may drive the transformation towards a more aggressive, androgen-insensitive phenotype.
  • Targeting bcl-2 with antisense oligos may inadvertently promote tumor progression and increased malignancy.
Keywords:
androgen receptorantisensebcl-2p300prostate cancertherapy

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