Role of SPTSSB-Regulated de Novo Sphingolipid Synthesis in Prostate Cancer Depends on Androgen Receptor Signaling

Area of Science:

• Oncology
• Biochemistry
• Molecular Biology

Background:

• Prostate cancer (PCa) therapies targeting androgen receptor (AR) signaling often fail.
• Treatment failure selects for aggressive AR-negative PCa cells with limited therapeutic options.

Purpose of the Study:

• To investigate the efficacy of ceramide nanoliposomes (CNLs) in treating AR-negative PCa.
• To elucidate the role of sphingolipid metabolism in PCa therapeutic resistance.

Main Methods:

• Administration of exogenous ceramide nanoliposomes (CNLs) to AR-positive and AR-negative cell lines.
• Evaluation of sphingolipid synthesis pathways, including SPTSSB expression.
• Pharmacological inhibition of AR and SPTSSB knockdown.

Main Results:

• CNLs demonstrated efficacy in AR-negative PCa cell lines.
• Anti-androgen therapy upregulates de novo sphingolipid synthesis via SPTSSB.
• Inhibition of AR enhanced CNL efficacy in AR-positive cells.
• SPTSSB knockdown reduced CNL efficacy in AR-negative cells.
• SPTSSB is upregulated in advanced PCa patients post-anti-androgen treatment.

Conclusions:

• AR signaling regulates sphingolipid metabolism in PCa.
• CNLs represent a potential therapeutic strategy for advanced PCa, particularly in AR-negative cases.
• Targeting SPTSSB may enhance CNL efficacy.