Suppression of prostate tumor cell survival by antisense oligonucleotide-mediated inhibition of AR-V7 mRNA synthesis

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Advanced prostate cancer often develops resistance to androgen deprivation therapy (ADT).
• This resistance is frequently mediated by C-terminally truncated androgen receptor (AR) variants, such as AR-V7, which arise from aberrant pre-mRNA splicing.
• AR-V7 lacks the ligand-binding domain, leading to constitutive transcriptional activity and promoting cancer progression.

Purpose of the Study:

• To design and evaluate antisense oligonucleotides (AONs) targeting cryptic splicing signals of the androgen receptor (AR) pre-mRNA.
• To assess the efficacy of these AONs in inhibiting the expression of the AR-V7 splice variant.
• To determine the therapeutic potential of AON-mediated AR-V7 suppression in castration-resistant prostate cancer (CRPC) models.

Main Methods:

• Design of two specific antisense oligonucleotides (AONs), AON-ISE and AON-ESE, targeting cryptic splicing signals in AR pre-mRNA.
• Assessment of AON efficiency in silencing AR-V7 splicing in CRPC cell lines (22Rv1, DuCaP, VCaP).
• Evaluation of the impact of AR-V7 downregulation on AR-V7-target gene expression (UBE2C), cell proliferation, and apoptosis.

Main Results:

• AON-ISE and AON-ESE demonstrated high efficiency in silencing AR-V7 splicing.
• These AONs did not affect the expression of full-length AR.
• Downregulation of AR-V7 led to reduced expression of the UBE2C gene, inhibited androgen-independent cell proliferation, and induced apoptosis in CRPC cell lines.

Conclusions:

• Splicing-directed AONs are effective in preventing the expression of the AR-V7 splice variant.
• This strategy offers a novel and attractive therapeutic option for treating castration-resistant prostate cancer (CRPC).
• Targeting aberrant AR splicing represents a promising approach to overcome ADT resistance in prostate cancer.