Testosterone accumulation in prostate cancer cells is enhanced by facilitated diffusion

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Testosterone drives prostate cancer (PC) growth through androgen receptor (AR) activation.
• Castration-resistant prostate cancer (CRPC) maintains intratumoral testosterone, indicating continued androgen-dependent growth.
• PC cells may regulate intracellular androgen levels via steroid metabolism enzymes and potentially testosterone entry.

Purpose of the Study:

• To investigate if testosterone enters cells via a transporter.
• To examine the role of UGT2B17 in regulating testosterone gradients and uptake.
• To analyze the expression of AKR1C3 in CRPC metastases and its microenvironment.

Main Methods:

• In vitro ³ H-testosterone uptake assays in LNCaP and PC3 cells.
• Modification of UGT2B17 levels to alter testosterone gradients and measurement of androgen levels.
• Analysis of AKR1C3 expression in CRPC metastases and tumor stroma.

Main Results:

• Testosterone uptake demonstrated saturable, temperature-dependent kinetics, indicative of facilitated transport.
• UGT2B17 levels correlated with testosterone transport, with suppression reducing uptake and overexpression enhancing it.
• AKR1C3 was expressed in both CRPC epithelial cells and the tumor microenvironment, with variable abundance across metastatic sites.

Conclusions:

• Facilitated testosterone uptake suggests a cell nonautonomous mechanism for androgen signaling in CRPC.
• The tumor microenvironment, in addition to tumor epithelium, can produce testosterone, contributing to CRPC progression.
• These findings highlight potential new therapeutic targets for managing castration-resistant prostate cancer.