Methylseleninic acid superactivates p53-senescence cancer progression barrier in prostate lesions of pten-knockout mouse

Lei Wang, Xiaolan Guo, Ji Wang, Cheng Jiang, Maarten C. Bosland, Junxuan Lü, Yibin Deng

Research output: Contribution to journalArticle

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Abstract

Monomethylated selenium (MM-Se) forms that are precursors of methylselenol, such as methylseleninic acid (MSeA), differ in metabolism and anticancer activities in preclinical cell and animal models from seleno-methionine that had failed to exert preventive efficacy against prostate cancer in North American men. Given that human prostate cancer arises from precancerous lesions such as high-grade prostatic intraepithelial neoplasia (HG-PIN), which frequently have lost phosphatase and tensin homolog (PTEN) tumor suppressor permitting phosphatidylinositol-3-OH kinase (PI3K)-protein kinase B (AKT) oncogenic signaling, we tested the efficacy of MSeA to inhibit HG-PIN progression in Pten prostatespecific knockout (KO) mice and assessed the mechanistic involvement of p53-mediated cellular senescence and of the androgen receptor (AR). We observed that short-term (4 weeks) oral MSeA treatment significantly increased expression of P53 and P21Cip1 proteins and senescence-associated-b-galactosidase staining, and reduced Ki67 cell proliferation index in Pten KO prostate epithelium. Long-term (25 weeks) MSeA administration significantly suppressed HG-PIN phenotype, tumor weight, and prevented emergence of invasive carcinoma in Pten KO mice. Mechanistically, the long-term MSeA treatment not only sustained P53-mediated senescence, but also markedly reduced AKT phosphorylation and AR abundance in the Pten KO prostate. Importantly, these cellular and molecular changes were not observed in the prostate of wild-type littermates which were similarly treated with MSeA. Because p53 signaling is likely to be intact in HG-PIN compared with advanced prostate cancer, the selective superactivation of p53-mediated 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.

Original languageEnglish (US)
Pages (from-to)35-42
Number of pages8
JournalCancer Prevention Research
Volume9
Issue number1
DOIs
StatePublished - Jan 2016

Fingerprint

Knockout Mice
Prostate
Prostatic Intraepithelial Neoplasia
Androgen Receptors
Neoplasms
Prostatic Neoplasms
Galactosidases
Proto-Oncogene Proteins c-akt
Cell Aging
Chemoprevention
Selenium
methylselenic acid
Tumor Burden
Phosphatidylinositol 3-Kinases
Phosphoric Monoester Hydrolases
Methionine
Epithelium
Animal Models
Phosphorylation
Cell Proliferation

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "Methylseleninic acid superactivates p53-senescence cancer progression barrier in prostate lesions of pten-knockout mouse",
abstract = "Monomethylated selenium (MM-Se) forms that are precursors of methylselenol, such as methylseleninic acid (MSeA), differ in metabolism and anticancer activities in preclinical cell and animal models from seleno-methionine that had failed to exert preventive efficacy against prostate cancer in North American men. Given that human prostate cancer arises from precancerous lesions such as high-grade prostatic intraepithelial neoplasia (HG-PIN), which frequently have lost phosphatase and tensin homolog (PTEN) tumor suppressor permitting phosphatidylinositol-3-OH kinase (PI3K)-protein kinase B (AKT) oncogenic signaling, we tested the efficacy of MSeA to inhibit HG-PIN progression in Pten prostatespecific knockout (KO) mice and assessed the mechanistic involvement of p53-mediated cellular senescence and of the androgen receptor (AR). We observed that short-term (4 weeks) oral MSeA treatment significantly increased expression of P53 and P21Cip1 proteins and senescence-associated-b-galactosidase staining, and reduced Ki67 cell proliferation index in Pten KO prostate epithelium. Long-term (25 weeks) MSeA administration significantly suppressed HG-PIN phenotype, tumor weight, and prevented emergence of invasive carcinoma in Pten KO mice. Mechanistically, the long-term MSeA treatment not only sustained P53-mediated senescence, but also markedly reduced AKT phosphorylation and AR abundance in the Pten KO prostate. Importantly, these cellular and molecular changes were not observed in the prostate of wild-type littermates which were similarly treated with MSeA. Because p53 signaling is likely to be intact in HG-PIN compared with advanced prostate cancer, the selective superactivation of p53-mediated 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.",
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Methylseleninic acid superactivates p53-senescence cancer progression barrier in prostate lesions of pten-knockout mouse. / Wang, Lei; Guo, Xiaolan; Wang, Ji; Jiang, Cheng; Bosland, Maarten C.; Lü, Junxuan; Deng, Yibin.

In: Cancer Prevention Research, Vol. 9, No. 1, 01.2016, p. 35-42.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Wang, Lei

AU - Guo, Xiaolan

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AU - Lü, Junxuan

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