Therapy-induced PSMA2 Sensitizes Prostate Cancer Cells to Residual Androgen and Promotes Neuroendocrine Lineage...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Research

Background:

• Aberrant androgen receptor (AR) signaling drives prostate cancer (PCa).
• Androgen deprivation therapy (ADT) and AR blockade are initial treatments, but castration-resistant prostate cancer (CRPC) and treatment-emergent neuroendocrine PCa (tNEPC) develop.
• The link between AR blockade and PCa lineage plasticity is not fully understood.

Purpose of the Study:

• Identify molecular mechanisms linking AR blockade to tNEPC evolution.
• Investigate the role of PSMA2 in prostate cancer treatment resistance and lineage plasticity.

Main Methods:

• Studied the effect of enzalutamide on PSMA2 expression in PCa cells.
• Investigated the impact of PSMA2 expression/silencing on AR signaling, HSP90 turnover, and androgen sensitivity.
• Assessed PSMA2's role in promoting tNEPC transcriptional and phenotypic conversion.

Main Results:

• Enzalutamide induces PSMA2 expression in AR-expressing PCa cells.
• PSMA2 accelerates HSP90 turnover, hypersensitizes AR to androgens, promotes AR activity in low-androgen conditions, and confers resistance to enzalutamide.
• PSMA2 silencing stabilizes HSP90, reduces androgen sensitivity, and re-sensitizes cells to enzalutamide.
• PSMA2 promotes lineage plasticity, driving conversion towards tNEPC.

Conclusions:

• PSMA2 is a stress-induced protein connecting AR blockade to tNEPC.
• PSMA2 maintains AR-dependent survival under ADT and drives neuroendocrine transition.
• PSMA2 represents a therapeutic target for intercepting the ADT-CRPC-tNEPC trajectory.