Spatial localization and pharmacodynamic assessment of intracrine androgen metabolism in CRPC xenograft tumor tissues upon active vitamin D treatment

Karl W Smith; Paul D Thompson; Faye L Cruickshank; C Logan Mackay; Diego F Cobice

doi:10.1007/s00216-026-06437-x

Spatial localization and pharmacodynamic assessment of intracrine androgen metabolism in CRPC xenograft tumor tissues upon active vitamin D treatment

Karl W Smith
, Paul D Thompson
, Faye L Cruickshank
, C Logan Mackay
, Diego F Cobice

University of Edinburgh

Research output: Contribution to journal › Article › peer-review

Abstract

Castrate-resistant prostate cancer (CRPC) progression is driven by intracrine androgen synthesis despite low circulating androgens. This study investigates the effects of active vitamin D (1,25-(OH)₂-D₃) on intracrine steroidogenesis in LNCaP xenograft tumors. Using mass spectrometry imaging, quantitative LC–MS/MS, and gene expression analyses, we demonstrate that vitamin D modulates androgen metabolism, reducing levels of potent androgen receptor ligands such as testosterone and dihydrotestosterone, while increasing hydroxylated androgen metabolites. Vitamin D treatment also suppresses AR-regulated gene expression and slows tumor growth compared to androgen precursor (DHEA) administration alone. Mass spectrometry imaging revealed widespread intracrine androgen production without distinct spatial localization within tumors at the image resolution analyzed. These findings suggest vitamin D disrupts androgen receptor signaling by altering intracrine androgen biosynthesis, supporting its potential as an adjunct therapy in CRPC management.

Original language	English
Pages (from-to)	3325-3337
Number of pages	13
Journal	Analytical and Bioanalytical Chemistry
Volume	418
Early online date	14 Mar 2026
DOIs	https://doi.org/10.1007/s00216-026-06437-x
Publication status	Published (in print/issue) - 30 Jun 2026

Bibliographical note

Publisher Copyright:
© The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2026.

Data Availability Statement

Data is available from the authors upon request.

Funding

We acknowledge funding from the Department for Employment and Learning (DEL) Northern Ireland and the Research Challenge Fund from Ulster University.

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Vitamin D treatment
Androgen metabolism
Mass spectrometry imaging
On-tissue chemical derivatization
Androgens/metabolism
Prostatic Neoplasms, Castration-Resistant/metabolism
Vitamin D/pharmacology
Humans
Male
Xenograft Model Antitumor Assays
Tandem Mass Spectrometry
Animals
Cell Line, Tumor
Chromatography, Liquid
Mice
Receptors, Androgen/metabolism

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10.1007/s00216-026-06437-x

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title = "Spatial localization and pharmacodynamic assessment of intracrine androgen metabolism in CRPC xenograft tumor tissues upon active vitamin D treatment",

abstract = "Castrate-resistant prostate cancer (CRPC) progression is driven by intracrine androgen synthesis despite low circulating androgens. This study investigates the effects of active vitamin D (1,25-(OH)₂-D₃) on intracrine steroidogenesis in LNCaP xenograft tumors. Using mass spectrometry imaging, quantitative LC–MS/MS, and gene expression analyses, we demonstrate that vitamin D modulates androgen metabolism, reducing levels of potent androgen receptor ligands such as testosterone and dihydrotestosterone, while increasing hydroxylated androgen metabolites. Vitamin D treatment also suppresses AR-regulated gene expression and slows tumor growth compared to androgen precursor (DHEA) administration alone. Mass spectrometry imaging revealed widespread intracrine androgen production without distinct spatial localization within tumors at the image resolution analyzed. These findings suggest vitamin D disrupts androgen receptor signaling by altering intracrine androgen biosynthesis, supporting its potential as an adjunct therapy in CRPC management.",

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AU - Smith, Karl W

AU - Thompson, Paul D

AU - Cruickshank, Faye L

AU - Mackay, C Logan

AU - Cobice, Diego F

N1 - Publisher Copyright: © The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature 2026.

PY - 2026/6/30

Y1 - 2026/6/30

N2 - Castrate-resistant prostate cancer (CRPC) progression is driven by intracrine androgen synthesis despite low circulating androgens. This study investigates the effects of active vitamin D (1,25-(OH)₂-D₃) on intracrine steroidogenesis in LNCaP xenograft tumors. Using mass spectrometry imaging, quantitative LC–MS/MS, and gene expression analyses, we demonstrate that vitamin D modulates androgen metabolism, reducing levels of potent androgen receptor ligands such as testosterone and dihydrotestosterone, while increasing hydroxylated androgen metabolites. Vitamin D treatment also suppresses AR-regulated gene expression and slows tumor growth compared to androgen precursor (DHEA) administration alone. Mass spectrometry imaging revealed widespread intracrine androgen production without distinct spatial localization within tumors at the image resolution analyzed. These findings suggest vitamin D disrupts androgen receptor signaling by altering intracrine androgen biosynthesis, supporting its potential as an adjunct therapy in CRPC management.

AB - Castrate-resistant prostate cancer (CRPC) progression is driven by intracrine androgen synthesis despite low circulating androgens. This study investigates the effects of active vitamin D (1,25-(OH)₂-D₃) on intracrine steroidogenesis in LNCaP xenograft tumors. Using mass spectrometry imaging, quantitative LC–MS/MS, and gene expression analyses, we demonstrate that vitamin D modulates androgen metabolism, reducing levels of potent androgen receptor ligands such as testosterone and dihydrotestosterone, while increasing hydroxylated androgen metabolites. Vitamin D treatment also suppresses AR-regulated gene expression and slows tumor growth compared to androgen precursor (DHEA) administration alone. Mass spectrometry imaging revealed widespread intracrine androgen production without distinct spatial localization within tumors at the image resolution analyzed. These findings suggest vitamin D disrupts androgen receptor signaling by altering intracrine androgen biosynthesis, supporting its potential as an adjunct therapy in CRPC management.

KW - Vitamin D treatment

KW - Androgen metabolism

KW - Mass spectrometry imaging

KW - On-tissue chemical derivatization

KW - Androgens/metabolism

KW - Prostatic Neoplasms, Castration-Resistant/metabolism

KW - Vitamin D/pharmacology

KW - Humans

KW - Male

KW - Xenograft Model Antitumor Assays

KW - Tandem Mass Spectrometry

KW - Animals

KW - Cell Line, Tumor

KW - Chromatography, Liquid

KW - Mice

KW - Receptors, Androgen/metabolism

UR - https://www.scopus.com/pages/publications/105033479839

U2 - 10.1007/s00216-026-06437-x

DO - 10.1007/s00216-026-06437-x

M3 - Article

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SN - 1618-2642

VL - 418

SP - 3325

EP - 3337

JO - Analytical and Bioanalytical Chemistry

JF - Analytical and Bioanalytical Chemistry

ER -

Spatial localization and pharmacodynamic assessment of intracrine androgen metabolism in CRPC xenograft tumor tissues upon active vitamin D treatment

Abstract

Bibliographical note

Data Availability Statement

Funding

UN SDGs

Keywords

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