Wang Lei, Guo Xiaolan, Wang Ji, Jiang Cheng, Bosland Maarten C, Lü Junxuan, Deng Yibin
Hormel Institute, University of Minnesota, Austin, Minnesota.
Department of Biomedical Sciences, Texas Tech University Health Sciences Center School of Pharmacy, Amarillo, Texas.
Cancer Prev Res (Phila). 2016 Jan;9(1):35-42. doi: 10.1158/1940-6207.CAPR-15-0236. Epub 2015 Oct 28.
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.
作为甲基硒醇前体的单甲基化硒（MM-Se）形式，如甲基亚硒酸（MSeA），在临床前细胞和动物模型中的代谢及抗癌活性，与在北美男性中未能对前列腺癌发挥预防功效的硒代蛋氨酸不同。鉴于人类前列腺癌起源于癌前病变，如高级别前列腺上皮内瘤变（HG-PIN），其经常缺失磷酸酶和张力蛋白同源物（PTEN）肿瘤抑制因子，从而允许磷脂酰肌醇-3-羟基激酶（PI3K）-蛋白激酶B（AKT）致癌信号传导，我们测试了MSeA抑制Pten前列腺特异性敲除（KO）小鼠中HG-PIN进展的功效，并评估了p53介导的细胞衰老及雄激素受体（AR）的机制参与情况。我们观察到，短期（4周）口服MSeA治疗显著增加了Pten KO前列腺上皮中P53和P21Cip1蛋白的表达以及衰老相关β-半乳糖苷酶染色，并降低了Ki67细胞增殖指数。长期（25周）给予MSeA显著抑制了Pten KO小鼠的HG-PIN表型、肿瘤重量，并预防了浸润性癌的出现。从机制上讲，长期MSeA治疗不仅维持了p53介导的衰老，还显著降低了Pten KO前列腺中AKT磷酸化和AR丰度。重要的是，在用MSeA进行类似处理的野生型同窝小鼠的前列腺中未观察到这些细胞和分子变化。由于与晚期前列腺癌相比，HG-PIN中的p53信号可能是完整的，MSeA对p53介导的衰老的选择性超激活表明了一种新的癌症化学预防模式，即通过诱导不可逆衰老并额外抑制AR和AKT致癌信号来加强癌症进展屏障。
