Methylseleninic Acid Superactivates p53-Senescence Cancer Progression Barrier in Prostate Lesions of Pten-Knockout Mouse.
Methylseleninic Acid Superactivates p53-Senescence Cancer Progression Barrier in Prostate Lesions of Pten-Knockout Mouse.
复制标题
DOI：
10.1158/1940-6207.capr-15-0236
复制
发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Deng Y
中科院分区：
文献类型：
--
作者：
Wang L;Guo X;Wang J;Jiang C;Bosland MC;Lü J;Deng Y
单甲基化硒（MM-Se）形式是甲基硒醇的前体，如甲基硒酸（MSeA），在临床前细胞和动物模型中的代谢和抗癌活性与硒蛋氨酸不同，硒蛋氨酸在北美男性中未能发挥预防前列腺癌（PCa）的功效。考虑到人类PCa源于癌前病变，如高级别前列腺上皮内瘤变（HG-PIN），这些病变经常失去PTEN肿瘤抑制因子，允许AKT致癌信号，我们在PTEN前列腺特异性敲除（KO）小鼠中测试了MSeA抑制HG-PIN进展的有效性，并评估了p53介导的细胞衰老和雄激素受体（AR）的机制参与。我们观察到短期（4周）口服MSeA显著增加Pten KO前列腺上皮中P53和P21Cip1蛋白的表达和衰老相关-β-半乳糖苷酶染色，降低Ki-67细胞增殖指数。长期（25周）给予MSeA可显著抑制Pten KO小鼠的HG-PIN表型、肿瘤重量，并防止侵袭性癌的出现。从机制上看，长期MSeA治疗不仅能维持p53介导的衰老，还能显著降低Pten KO前列腺中AKT磷酸化和AR丰度。重要的是，这些细胞和分子的变化没有观察到野生型幼崽的前列腺，同样用MSeA治疗。由于与晚期PCa相比，p53信号在HG-PIN中可能是完整的，因此MSeA对p53介导的衰老的选择性超激活提示了一种新的癌症化学预防模式，即通过诱导不可逆的衰老来加强癌症进展屏障，同时额外抑制AR和AKT致癌信号。
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. Given that human PCa arises from precancerous lesions such as high-grade prostatic intraepithelial neoplasia (HG-PIN) which frequently have lost PTEN tumor suppressor permitting 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 Ki-67 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. Since p53 signaling is likely to be intact in HG-PIN compared to advanced PCa, the selective super-activation 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.