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Coulter, Amarillo, TX Monomethylated selenium MM-Se forms that are precursors of methylselenol such as methylseleninic acid MSeA differ in metabolism and anti-cancer activities in preclinical cell and animal models from seleno-methionine that had failed to exert preventive efficacy against prostate cancer PCa in North American men. Importantly, these cellular and molecular changes were not observed in the prostate of wild type littermates which were similarly treated with MSeA.

Since p53 signaling is likely to be intact in HG-PIN compared to advanced PCa, the selective super-activation of pmediated senescence by MSeA suggests a new paradigm of cancer chemoprevention by strengthening a cancer progression barrier through induction of irreversible senescence with additional suppression of AR and AKT oncogenic signaling. Selenium Se compounds have been studied for their chemopreventive potential in various animal models of carcinogenesis, notably mammary, colon, lung, and prostate cancer.

Selenized yeast Se-yeast and its principal Se form Se-methionine SeMet have been tested in several human trials in North America for the prevention of prostate cancer PCa 1 — 4.

Many, including us, have opined on the possible reasons for such failures 5 — 7 8. One key factor was the selection of ineffective Se agents.

In fact, the scarce animal efficacy data that existed prior to the initiation of these trials did not support PCa preventive efficacy of SeMet and these negative data were not published in full-length until after SELECT was terminated 9 Preclinical and mechanistic research has demonstrated that SeMet has little in common with the mono-methylated methylselenol precursor Se forms MM-Sesuch as methylseleninic acid MSeAin terms of metabolism and anti-cancer activities 8 We have posited that the failure of SeMet should not be taken to indicate that other Se forms are ineffective for PCa chemoprevention Indeed, we have shown that daily orally-administered MSeA inhibited the growth of DU and PC-3 human PCa xenografts in athymic nude mice whereas an equal Se dose of SeMet was inactive, in spite of SeMet leading to much higher retention of Se in the xenograft tumors We also reported the efficacy of MSeA to inhibit prostate carcinogenesis in the transgenic adenocarcinoma mouse prostate TRAMP model which improved survival with no observable long-term adverse effect More efficacy and biomarker assessments in clinically-relevant prostate carcinogenesis models with MM-Se will be essential to evaluate their PCa chemoprevention potential in the post-SELECT era to support future translation of these data to humans.

Mouse genetic studies have demonstrated that loss of Pten in prostate epithelium rapidly causes HG-PIN that ultimately progresses to invasive adenocarcinoma and metastatic disease As men diagnosed with HG-PIN are at increased risk of developing PCa, this prostate specific conditional Pten KO mouse model recapitulates essential characteristics of human prostate carcinogenesis and is considered clinically relevant for studies of PCa chemoprevention.

In the Pten KO model, the sustained activation of AKT not only initiates and perpetuates oncogenic signaling and progression pathways, but at the same time induces cellular senescence known as P ten-deficiency I nduced C ellular S enescence PICSwhich acts as a formidable barrier to restrain oncogenic progression to invasive and metastatic disease 16 The critical role of androgen receptor AR signaling in PCa, even at the advanced metastatic castration-resistant stage, is well established and therapeutically exploited Unfortunately, recent studies have shown that inhibition of AR signaling by castration or antagonist drugs inadvertently promotes the progression of stable HG-PIN to invasive carcinomas in Pten KO model 19raising concerns for utilization of these androgen deprivation strategies for chemoprevention in high risk men and PCa patients with PTEN deficiency or mutations.

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AIN93G semi-purified diet and water were provided ad libitum. Mouse body weight was monitored weekly. At necropsy, total prostate was dissected, photographed and weighed. The long-term experiment was carried out with same design, except that the mice were weeks old at the start of the MSeA and water treatments 5 days per weeklasting for 25 weeks 8 mice per group.

At necropsy, the genitourinary GU tract was collected and weighed. Then the different prostate lobes were dissected and weighed. The prostate lobes were saved and processed individually for histopathology and biochemical analyses. Tissue processing and staining were as performed previously 12 The pathological changes of all lobes of prostate were classified according to Shapell et al.

The sections were stained for SA-gal and counterstained with eosin, as described previously IHC and immunoblot Western were performed as previously described Images were captured and analyzed by ImagePro-Plus 6. Pooling of prostate tissues from the short-term experiment was necessary due to limited amount of material available. For parametric data, the mean and SEM were calculated for each experimental group. For comparison of only 2 groups, student t-test was used. In the first experiment, we evaluated the effect of 4-week MSeA treatment to identify early biochemical and cellular changes that might correlate and predict its long-term preventive efficacy against HG-PIN growth and tumor progression in Pten KO mice.

As shown in Fig. MSeA or water treatment commenced at 12 weeks of age. Tubulin served as loading control. For Ki, percentage of positive nuclei in the prostate epithelium was quantified.

However, in the prostate of MSeA-treated Pten KO mice, the staining intensity was remarkably elevated in the epithelial cells by as much as 4 fold, estimated by ImagePro-Plus software Fig. The promising biochemical and cellular responses to the short-term MSeA intervention prompted us to evaluate its chemopreventive efficacy on Pten KO HG-PIN growth and progression in the second experiment with week administration. At the gross anatomical level, blood-rich prostate tumors were visible in some water-treated control Pten KO mice Supplement Fig.

MSeA or water treatment commenced at 10 weeks of age. In contrast, MSeA-treated mice showed dramatic histopathological modification, many approaching near normal appearance of the prostate of the WT mice and none of them with detectable invasive adenocarcinoma features Fig.

Consistent with selectivity of targeting oncogenic growth, MSeA treatment of WT mice did not affect their typical normal glandular structures Fig. Effect of long-term MSeA supplementation on p-Akt and androgen receptor ARsenescence and cellular proliferative index in the anterior prostate of mice in Figure 3.

C Quantitation of changes from A and B. Two mice per group were randomly chosen for analyses.

B Schematic illustration of temporal sequence of cellular and molecular events in Pten KO prostate carcinogenesis and the entry points of MSeA actions. To our best knowledge, this study is the first in which any form of Se has been tested in the Pten KO PCa mouse model for chemopreventive efficacy.

In addition to boosting and sustaining PP21Cip1 senescence as a cell proliferation barrier, long-term treatment with MSeA led to considerably reduced tumor burden Fig.

Since p53 signaling is more likely to be intact in precancerous lesions than advanced PCa, the super-activation of psenescence by MSeA offers a new paradigm for PCa chemoprevention through strengthening a cancer progression barrier in the precursor lesions. The in vivo mechanisms mediating these cellular and molecular actions of MSeA are currently be elucidated. The efficacy for chemoprevention of Pten -deficient HG-PIN progression by MSeA documented in the current work and the previously demonstrated efficacy and safety of MSeA in other prostate cancer mouse models 12 13 provide strong justification for further development of MM-Se toward human translational studies.

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Grants R21 CA Y. Disclosure of Potential Conflicts of Interest: All authors have no personal or financial conflict of interest and have not entered into any agreement that could interfere with our access to the data on the research or on our ability to analyze the data independently, to prepare articles, and to publish them.

National Center for Biotechnology InformationU. Cancer Prev Res Phila. Author manuscript; available in PMC Jan 1. Author information Copyright and License information Disclaimer. Coulter St, Amarillo, TX The publisher’s final edited version of this article is available free at Cancer Prev Res Phila.

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See other articles in PMC that cite the published article. Associated Data Supplementary Materials 1. Abstract Monomethylated selenium MM-Se forms that are precursors of methylselenol such as methylseleninic acid MSeA differ in metabolism and anti-cancer activities in preclinical cell and animal models from seleno-methionine that had failed to exert preventive efficacy against prostate cancer PCa in North American men.

Histopathology analysis Tissue processing and staining were as performed previously 12 Statistical analyses For parametric data, the mean and SEM were calculated for each experimental group. Open in a separate window.

Supplementary Material 1 Click here to view. Footnotes Disclosure of Potential Conflicts of Interest: Effects of selenium supplementation for cancer prevention in patients with carcinoma of the skin.

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A randomized controlled trial. Nutritional Prevention of Cancer Study Group. Phase 3 clinical trial investigating the effect of selenium supplementation in men at high-risk for prostate cancer.

Effect of selenium and vitamin E on risk of prostate cancer and other cancers: Cancer Prev Res Phila ; 4: Selenium and prostate cancer prevention: Cancer Prev Res Phila ; 7: Cancer Prevention with Selenium: Lwi, Oxidative Stress and Cancer. Selenomethionine and alpha-tocopherol do not inhibit prostate carcinogenesis in the testosterone plus estradiol-treated NBL rat model. Cancer Prev Res Phila ; 3: Null activity of selenium and vitamin e as cancer chemopreventive agents in the rat prostate.

Lu J, Jiang C. Selenium and cancer chemoprevention: Methyl-selenium compounds llei prostate carcinogenesis in the transgenic adenocarcinoma of mouse prostate model with survival benefit. Cancer Prev Res Phila ; 2: Superior in vivo inhibitory efficacy of methylseleninic acid against human prostate cancer over selenomethionine or selenite.

The functions and regulation of the PTEN tumour suppressor. Nature reviews Molecular cell biology. Prostate-specific deletion of the murine Pten tumor suppressor gene leads to metastatic prostate cancer.

A novel type of cellular senescence that can be enhanced in mouse models and human tumor xenografts to suppress prostate tumorigenesis. The Journal of clinical investigation. Crucial role of pdependent cellular senescence in suppression of Pten-deficient tumorigenesis. Maintaining and reprogramming genomic androgen receptor activity in prostate cancer.

Opposing effects 1188 androgen deprivation and targeted therapy on prostate cancer prevention. Methyl selenium metabolites decrease prostate-specific antigen expression by inducing protein degradation and suppressing androgen-stimulated transcription. Prostate specific antigen expression is down-regulated by selenium through disruption of androgen receptor signaling.