Mayo Clinic - AuthorCitation

Methyl selenium metabolites decrease prostate-specific antigen expression by inducing protein degradation and suppressing androgen-stimulated transcription

Cho, Sung Dae, Jiang, Cheng , Malewicz, Barbara, Kang, Kyung‐Sun , Lee, Yong-Soon, Ip, Clement, Dong, Yan , Young, Charles Y.F. , Lü, Junxuan

Molecular Cancer Therapeutics | June 8, 2022 | Volume: 3 | Issue: 5 | Pages: 605-612

10.1158/1535-7163.605.3.5

Abstract Prostate-specific antigen (PSA) is widely used clinically for prostate cancer diagnostics and as an indicator of therapeutic efficacy and recurrence. Several human chemoprevention trials are being conducted to validate the prostate cancer prevention efficacy of selenium and PSA is used in these trials as a biomarker of response. A better understanding of the effects of selenium metabolites on the kinetics of PSA turnover and secretion in prostate cancer cells treated with selenium at concentrations which are achievable physiologically will be important for interpreting the results of these trials. This study addresses whether the putative active anticancer selenium metabolite methylselenol or its precursor methylseleninic acid (MSeA) specifically inhibits PSA expression in the androgen-responsive LNCaP prostate cancer cell model. The results show that exposure to sub-apoptotic concentrations of MSeA and methylselenol inhibited PSA protein expression and secretion, whereas sodium selenite and selenomethionine lacked inhibitory effect. The inhibition was detectable at 3 h of exposure and required a threshold level of MSeA to sustain. Turnover experiments showed that MSeA caused rapid PSA degradation, which was partially blocked by lysosomal inhibitors, but not by a proteasomal inhibitor. Furthermore, MSeA treatment reduced PSA mRNA level, down-regulated androgen receptor protein expression, and inhibited androgen-stimulated PSA promoter transcription. In summary, methylselenol or MSeA specifically and rapidly inhibited PSA expression through two mechanisms of action: inducing PSA protein degradation and suppressing androgen-stimulated PSA transcription. These findings may have important mechanistic implications for the prostate specific cancer chemopreventive action of selenium.

Highly Sensitive Automated Chemiluminometric Assay for Measuring Free Human Glandular Kallikrein-2

Klee, George G., Goodmanson, Marcia K., Jacobsen, Steven J. , Young, Charles YF, Finlay, Judith A., Rittenhouse, Harry G., Wolfert, Robert L., Tindall, Donald J.

Clinical Chemistry | January 23, 2020 | Volume: 45 | Issue: 6 | Pages: 800-806

10.1093/clinchem/45.6.800

AbstractBackground: Human glandular kallikrein (hK2) is a serine protease that has 79% amino acid identity with prostate-specific antigen (PSA). Both free hK2 and hK2 complexed to α1-antichymotrypsin (ACT) are present in the blood in low concentrations. We wished to measure hK2 in serum with limited contribution from hK2-ACT for the results.Methods: We developed an automated assay for hK2 with use of a select pair of monoclonal antibodies. The prototype assay was implemented on a Beckman Coulter ACCESS® analyzer.Results: The detection limit of the assay was 1.5 ng/L, the “functional sensitivity” (day-to-day CV <15%) was <4 ng/L, cross-reactivity with PSA and PSA-ACT was negligible, and cross-reactivity with hK2-ACT was 2%. After surgical removal of prostate glands, serum hK2 was <7 ng/L and was <15 ng/L in most healthy women. The median serum concentration of hK2 in healthy men without prostate cancer was 26 ng/L. The median concentration of hK2 was 72 ng/L for men having prostate cancer with lower Gleason scores compared with 116 ng/L for men with more advanced cancer. The concentration of hK2 correlated weakly with PSA, with the mean hK2 concentrations generally 30- to 80-fold lower than PSA concentrations.Conclusion: The availability of a robust, high sensitivity automated assay for hK2 should facilitate further investigations of the role of hK2 measurements in the management of patients with prostate disease.

In Situ Hybridization of Prostate-Specific Antigen mRNA in Human Prostate

Qiu, Shu-Dong, Bilhartz, David L., Prescott, James L. , Farrow, George M., He, Wei-Wu, Tindall, Donald J., Young, Charles Y.F.

Journal of Urology | June 29, 2017 | Volume: 144 | Issue: 6 | Pages: 1550-1556

10.1016/s0022-5347(17)39797-5 | PMID 1700164

Hogen, Kristine L., Tindall, D. J., Young, Charles Y.F.

The Japanese Journal of Urology | April 6, 2017 | Volume: 86 | Issue: 3 | Pages: 427

10.5980/jpnjurol.86.427_2

Shared Decision Making in the Emergency Department Among Patients With Limited Health Literacy: Beyond Slower and Louder

Griffey, Richard T. , McCarthy, Danielle M. , Shelton, Erica , Castaneda‐Guarderas, Ana, Young‐Brinn, Angela, Fowler, Donna, Grudszen, Corita, Castañeda-Guarderas, Ana, McNaughton, Candace D , Griffey, Richard T

Academic Emergency Medicine | September 19, 2016 | Volume: 23 | Issue: 12 | Pages: 1403-1409

10.1111/acem.13104 | PMID 27641236

AbstractAlthough studies suggest that patients with limited health literacy and/or low numeracy skills may stand to gain the most from shared decision making (SDM), the impact of these conditions on the effective implementation of SDM in the emergency department (ED) is not well understood. In this article from the proceedings of the 2016 Academic Emergency Medicine Consensus Conference on Shared Decision Making in the Emergency Department we discuss knowledge gaps identified and propose consensus‐driven research priorities to help guide future work to improve SDM for this patient population in the ED.

Adapting Conceptual Frameworks for Patient Engagement in Emergency Department Research

Carden, Donna L., Booker‐Vaughns, Juanita , Dunn, Patrick , Kizzie-Gillett, Constance L., Vaughan, William P., Weingarten, Gail, Williams, Pluscedia, Young‐Brinn, Angela, Grudzen, Corita R. , Wright, Rebecca , Hess, Erik P.

Academic Emergency Medicine | August 16, 2016 | Volume: 23 | Issue: 12 | Pages: 1332-1336

10.1111/acem.13066 | PMID 27526646

AbstractFor many people the emergency department (ED) is the first point of access to healthcare for acute needs and a recurring location for many with chronic healthcare needs. While the ED is well placed to identify unmet needs it can also be a net that people slip through when faced with uncoordinated and expensive healthcare challenges. Thus the ED has a responsibility to set patients on a safe and meaningful care trajectory, which can only be done in consultation and partnership with the patients themselves. The purpose of this article is to present crucial aspects of patient engagement that are essential for future research to foster an environment of colearning and respect that encourages ongoing involvement by patients, families, and staff.

Preclinical Evaluation of the Supercritical Extract of Azadirachta Indica (Neem) Leaves In Vitro and In Vivo on Inh

Bergen, H. Robert, Cheville, John C. , Karnes, R. Jeffrey , Cao, Hong , Tindall, Donald J., McNiven, Mark A. , Donkena, Krishna Vanaja, Wu, Qiang , Kohli, Manish , Young, Charles Y.F.

Molecular Cancer Therapeutics | March 28, 2014 | Volume: 13 | Issue: 5 | Pages: 1067-1077

10.1158/1535-7163.mct-13-0699 | PMID 24674886

Abstract Azadirachta indica, commonly known as neem, has gained worldwide prominence because of its medical properties, namely antitumor, antiviral, anti-inflammatory, antihyperglycemic, antifungal, and antibacterial activities. Despite these promising results, gaps remain in our understanding of the molecular mechanism of action of neem compounds and their potential for use in clinical trials. We investigated supercritical extract of neem leaves (SENL) for the following: molecular targets in vitro, in vivo efficacy to inhibit tumor growth, and bioactive compounds that exert antitumor activity. Treatment of LNCaP-luc2 prostate cancer cells with SENL suppressed dihydrotestosterone-induced androgen receptor and prostate-specific antigen levels. SENL inhibited integrin β1, calreticulin, and focal adhesion kinase activation in LNCaP-luc2 and PC3 prostate cancer cells. Oral administration of SENL significantly reduced LNCaP-luc2 xenograft tumor growth in mice with the formation of hyalinized fibrous tumor tissue, reduction in the prostate-specific antigen, and increase in AKR1C2 levels. To identify the active anticancer compounds, we fractionated SENL by high-pressure liquid chromatography and evaluated 16 peaks for cytotoxic activity. Four of the 16 peaks exhibited significant cytotoxic activity against prostate cancer cells. Mass spectrometry of the isolated peaks suggested the compounds with cytotoxic activity were nimbandiol, nimbolide, 2′,3′-dihydronimbolide, and 28-deoxonimbolide. Analysis of tumor tissue and plasma samples from mice treated with SENL indicated 28-deoxonimbolide and nimbolide as the bioactive compounds. Overall, our data revealed the bioactive compounds in SENL and suggested that the anticancer activity could be mediated through alteration in androgen receptor and calreticulin levels in prostate cancer. Mol Cancer Ther; 13(5); 1067–77. ©2014 AACR.

Interactive Effects of Triiodothyronine and Androgens on Prostate Cell Growth and Gene Expression*

Zhang, Shaobo , Hsieh, Ming-Li , Zhu, Wen, Klee, George G., Tindall, Donald J., Young, Charles Y.F.

Endocrinology | January 8, 2014 | Volume: 140 | Issue: 4 | Pages: 1665-1671

10.1210/endo.140.4.6666 | PMID 10098501

A Nonsteroidal Anti-Inflammatory Drug, Flufenamic Acid, Inhibits the Expression of the Androgen Receptor in LNCaP Cells

Zhu, Wen, Smith, Aaron L., Young, Charles Y.F.

Endocrinology | January 8, 2014 | Volume: 140 | Issue: 11 | Pages: 5451-5454

10.1210/endo.140.11.7246 | PMID 10537180

Phenethyl isothiocyanate inhibits androgen receptor‐regulated transcriptional activity in prostate cancer cells through suppressing PCAF

Yu, Chun-Guang, Gong, Ai‐Yu, Chen, Dongqing , Leon, Daniel Solelo, Young, Charles YF, Chen, Xianming

Molecular Nutrition & Food Research | May 10, 2013 | Volume: 57 | Issue: 10 | Pages: 1825-1833

10.1002/mnfr.201200810 | PMID 23661605

ScopeAndrogen receptor (AR) signaling is critical for all aspects of prostate growth and tumorigenesis. The glucosinolate‐derived phenethyl isothiocyanate (PEITC) has recently been demonstrated to reduce the risk of prostate cancer (PCa) and inhibit PCa cell growth. We previously reported that p300/CBP‐associated factor (PCAF), a co‐regulator for AR, is upregulated in PCa cells through suppression of the mir‐17 gene. Here, we assessed the effects of PEITC on PCAF expression and AR‐regulated transcriptional activity in PCa cells.Methods and resultsUsing AR‐responsive LNCaP cells, we observed the inhibitory effects of PEITC on the dihydrotestosterone‐stimulated AR transcriptional activity and cell growth of PCa cells. Interestingly, overexpression of PCAF attenuated the inhibitory effects of PEITC on dihydrotestosterone‐stimulated AR transcriptional activity. Expression of PCAF was upregulated in PCa cells through suppression of miR‐17. PEITC treatment significantly decreased PCAF expression and promoted transcription of miR‐17 in LNCaP cells. Functional inhibition of miR‐17 attenuated the suppression of PCAF in cells treated by PEITC.ConclusionOur results indicate that PEITC inhibits AR‐regulated transcriptional activity and cell growth of PCa cells through miR‐17‐mediated suppression of PCAF, suggesting a new mechanism by which PEITC modulates PCa cell growth.

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