Methylseleninic Acid Superactivates p53-Senescence Cancer Progression Barrier in Prostate Lesions of Pten-Knockout Mouse.
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 prostate-specific 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-β-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.
Hormel Institute, University of Minnesota, Austin, Minnesota.
Lei
L
Wang
Hormel Institute, University of Minnesota, Austin, Minnesota.
Xiaolan
X
Guo
Hormel Institute, University of Minnesota, Austin, Minnesota.
Ji
J
Wang
Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas.
Cheng
C
Jiang
Department of Pathology, University of Illinois at Chicago (UIC) College of Medicine, Chicago, Illinois.
Maarten C
MC
Bosland
Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas. yideng@hi.umn.edu junxuanlu@hmc.psu.edu.
Junxuan
J
Lü
Hormel Institute, University of Minnesota, Austin, Minnesota. yideng@hi.umn.edu junxuanlu@hmc.psu.edu.
Yibin
Y
Deng
D000284:Administration, Oral; D000818:Animals; D016922:Cellular Senescence; D004195:Disease Models, Animal; D018450:Disease Progression; D004848:Epithelium / Q000378:metabolism; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016566:Organoselenium Compounds / Q000737:chemistry*; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011467:Prostate / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D011897:Random Allocation; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D016566:Organoselenium Compounds; D016159:Tumor Suppressor Protein p53; C008493:methylselenic acid; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse