Androgen-ablative therapies inducing CXCL8 regulates mTORC1/SREBP2-dependent cholesterol biosynthesis to support...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Androgen-ablative therapies (AATs) are standard for prostate cancer (PCa).
• AATs inhibit androgen receptor-positive (AR+) PCa but can promote androgen receptor-negative (AR-) PCa.
• Mechanisms driving AR- PCa progression under AAT remain unclear.

Purpose of the Study:

• To elucidate the mechanisms underlying the increase in AR- PCa cell subtypes following AAT.
• To identify key molecular effectors driving AR- PCa cell survival and tumorigenicity.

Main Methods:

• Investigated cell type proportion changes in response to AAT.
• Utilized CXCL8 (interleukin-8) depletion and inhibition assays.
• Analyzed signaling pathways including mTORC1 and SREBP2 activation.
• Assessed de novo cholesterol synthesis.

Main Results:

• Androgen ablation suppressed AR signaling, upregulating CXCL8 gene transcription.
• CXCL8 depletion or inhibition impaired AR- PCa cell survival.
• CXCL8 activated the mTORC1 pathway, enhancing de novo cholesterol synthesis via SREBP2.
• The CXCL8-mTORC1-SREBP2 axis was identified as crucial for AR- PCa tumorigenicity.

Conclusions:

• CXCL8 is a critical effector for AR- PCa cell survival under AAT.
• The CXCL8-mTORC1-SREBP2 signaling axis promotes AR- PCa progression.
• Targeting this axis may offer novel therapeutic strategies for advanced prostate cancer.