Isoform-specific Activities of Androgen Receptor and its Splice Variants in Prostate Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Androgen receptor (AR) signaling drives castration-resistant prostate cancer (CRPC) despite androgen deprivation therapy (ADT).
• Shorter AR variants (ARv7, ARv567es), lacking the ligand-binding domain, are expressed in CRPC and may enable cancer cells to evade ADT.
• It remains unclear if these AR variants function as diminished versions of AR or possess distinct, isoform-specific activities.

Purpose of the Study:

• To investigate the similarities and differences in transcriptomic, metabolomic, and lipidomic profiles induced by the activation of full-length AR, ARv7, and ARv567es.
• To determine if AR variants mediate unique downstream activities distinct from full-length AR.

Main Methods:

• Utilized LNCaP prostate cancer cell lines engineered for inducible expression of AR, ARv7, or ARv567es.
• Performed comparative analyses of transcriptomics, metabolomics, and lipidomics across cells expressing each AR isoform.
• Validated some findings in a VCaP cell line model.

Main Results:

• Identified largely similar gene regulation by all three AR isoforms, but also detected distinct transcriptomic activities between full-length AR and the variants.
• Observed specific differences in gene regulation between ARv7 and ARv567es.
• Metabolomic and lipidomic analyses in LNCaP cells revealed further differences in downstream activities mediated by the AR isoforms.

Conclusions:

• Shorter AR variants are not merely weaker substitutes for full-length AR.
• These AR variants possess the capability to mediate unique downstream activities.
• Some of these unique activities are specific to individual AR variants, suggesting distinct functional roles in CRPC progression.