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Inhibitory Interplay of SULT2B1b Sulfotransferase with AKR1C3 Aldo-keto Reductase in Prostate Cancer
Sulgi Park1,2,3, Chung-Seog Song1,3, Chun-Lin Lin1
1Department of Molecular Medicine, University of Texas Health San Antonio, San Antonio, Texas.
Abstract:
SULT2B1b (SULT2B) is a prostate-expressed hydroxysteroid sulfotransferase, which may regulate intracrine androgen homeostasis by mediating 3β-sulfation of dehydroepiandrosterone (DHEA), the precursor for 5α-dihydrotestosterone (DHT) biosynthesis. The aldo-keto reductase (AKR)1C3 regulates androgen receptor (AR) activity in castration-resistant prostate cancer (CRPC) by promoting tumor tissue androgen biosynthesis from adrenal DHEA and also by functioning as an AR-selective coactivator. Herein we report that SULT2B-depleted CRPC cells, arising from stable RNA interference or gene knockout (KO), are markedly upregulated for AKR1C3, activated for ERK1/2 survival signal, and induced for epithelial-to-mesenchymal (EMT)-like changes. EMT was evident from increased mesenchymal proteins and elevated EMT-inducing transcription factors SNAI1 and TWIST1 in immunoblot and single-cell mass cytometry analyses. SULT2B KO cells showed greater motility and invasion in vitro; growth escalation in xenograft study; and enhanced metastatic potential predicted on the basis of decreased cell stiffness and adhesion revealed from atomic force microscopy analysis. While AR and androgen levels were unchanged, AR activity was elevated, since PSA and FKBP5 mRNA induction by DHT-activated AR was several-fold higher in SULT2B-silenced cells. AKR1C3 silencing prevented ERK1/2 activation and SNAI1 induction in SULT2B-depleted cells. SULT2B was undetectable in nearly all CRPC metastases from 50 autopsy cases. Primary tumors showed variable and Gleason score (GS)-independent SULT2B levels. CRPC metastases lacking SULT2B expressed AKR1C3. Since AKR1C3 is frequently elevated in advanced prostate cancer, the inhibitory influence of SULT2B on AKR1C3 upregulation, ERK1/2 activation, EMT-like induction, and on cell motility and invasiveness may be clinically significant. Pathways regulating the inhibitory SULT2B-AKR1C3 axis may inform new avenue(s) for targeting SULT2B-deficient prostate cancer.
Insights
Sulfotransferase SULT2B1b (SULT2B) normally inhibits prostate cancer progression by suppressing AKR1C3. Loss of SULT2B in castration-resistant prostate cancer (CRPC) promotes AKR1C3 upregulation, driving metastasis and invasiveness.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Sulfotransferase SULT2B1b (SULT2B) regulates intracrine androgen homeostasis via dehydroepiandrosterone (DHEA) sulfation.
- Aldo-keto reductase 1C3 (AKR1C3) promotes androgen receptor (AR) activity in castration-resistant prostate cancer (CRPC) by enhancing androgen biosynthesis and coactivating AR.
Purpose of the Study:
- To investigate the role of SULT2B in regulating AKR1C3 expression and its downstream effects in CRPC.
- To explore the potential clinical significance of the SULT2B-AKR1C3 axis in prostate cancer progression and metastasis.
Main Methods:
- Stable RNA interference and gene knockout (KO) to deplete SULT2B in CRPC cells.
- Immunoblotting, single-cell mass cytometry, and atomic force microscopy to assess protein expression, EMT markers, cell motility, invasion, and stiffness.
- Xenograft studies to evaluate tumor growth and metastatic potential.
- Analysis of SULT2B and AKR1C3 expression in human CRPC autopsy samples.
Main Results:
- SULT2B depletion in CRPC cells led to marked upregulation of AKR1C3, activation of ERK1/2 survival signaling, and induction of epithelial-to-mesenchymal (EMT)-like changes.
- SULT2B KO cells exhibited increased motility, invasion, growth, and metastatic potential, correlated with decreased cell stiffness and adhesion.
- AR activity was elevated in SULT2B-silenced cells, despite unchanged AR and androgen levels.
- AKR1C3 silencing abrogated ERK1/2 activation and SNAI1 induction in SULT2B-depleted cells.
- SULT2B was undetectable in most CRPC metastases, which frequently expressed AKR1C3.
Conclusions:
- SULT2B exerts an inhibitory influence on AKR1C3 upregulation, thereby suppressing CRPC cell activation, EMT, motility, and invasiveness.
- The loss of SULT2B in CRPC metastases suggests a role in promoting advanced disease progression.
- Targeting the SULT2B-AKR1C3 axis represents a potential therapeutic strategy for SULT2B-deficient prostate cancer.
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