Stimulation of cellular senescent processes, including secretory phenotypes and anti-oxidant responses, after androgen deprivation therapy in human prostate cancer
Stimulation of cellular senescent processes, including secretory phenotypes and anti-oxidant responses, after androgen deprivation therapy in human prostate cancer
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DOI：
10.1016/j.jsbmb.2016.06.007
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发表时间：
2017-01-01
影响因子：
4.1
通讯作者：
Tanaka, Akira
中科院分区：
文献类型：
--
作者：
Kawata, Hirotoshi;Kamiakito, Tomoko;Tanaka, Akira
内分泌抵抗是前列腺癌的一个主要问题。最近的研究表明，细胞可塑性在治疗抵抗中起着关键作用。然而，人们对雄激素剥夺治疗（ADT）后人类前列腺癌细胞的变化知之甚少。在这项研究中，我们研究了细胞衰老、衰老相关分泌表型（SASPs）和抗氧化反应。在小鼠去势模型中，激素消融上调前列腺中衰老相关(SA)- β - gal活性，以及p27（KIP1）和p53的表达。与此相一致，ADT后人类非病理性前列腺中p21（CIP1）和p27（KIP1）的表达明显高于未处理标本。在一项SASP标记物的研究中，与未处理的标本相比，ADT后人类非病理性前列腺中IL6和IL8的表达也更高。在ADT后切除的人前列腺癌标本中，IL6、IL8和MMP2的表达比未治疗的肿瘤更强烈。值得注意的是，抗氧化试剂NAC显著抑制雄激素敏感的人前列腺癌LNCaP细胞中的sa - β - gal活性。在抗氧化反应基因的免疫组化分析中，ADT后人类前列腺和癌标本中激素消融后NRF2和NQO1的表达高于未处理标本或去势后小鼠前列腺。综上所述，这些发现表明ADT诱导细胞衰老过程伴随着分泌表型和前列腺抗氧化反应。这些细胞变化可能是预防前列腺癌内分泌抵抗的有吸引力的靶点。(C) 2016 Elsevier Ltd.版权所有。
Endocrine resistance is a major problem in prostate cancer. Recent studies suggest that cellular plasticity plays a key role in therapy resistance. Yet little is known about the cellular changes of human prostate cancer after androgen deprivation therapy (ADT). In this study, we investigated cellular senescence, senescence-associated secretory phenotypes (SASPs), and anti-oxidant responses. Hormone ablation upregulated senescence-associated (SA)-beta-Gal activity in prostate glands, as well as the expressions of p27(KIP1) and p53, in a mouse castration model. In line with this, the expressions of p21(CIP1) and p27(KIP1) were significantly more upregulated in human non-pathological prostatic glands after ADT than in untreated specimens. In a study of SASP markers, the expressions of IL6 and IL8 were also more upregulated in human non-pathological prostatic glands after ADT than in untreated specimens. IL6, IL8, and MMP2 were expressed more strongly in human prostate cancer specimens resected after ADT than in untreated tumors. Of note, treatment with the anti-oxidant reagent NAC significantly suppressed SA-beta-Gal activity in androgen-sensitive human prostate cancer LNCaP cells. In immunohistochemical analyses on anti-oxidant response genes, NRF2 and NQO1 were more upregulated after hormone ablation in human prostate gland and carcinoma specimens after ADT than in untreated specimens or in murine prostate glands after castration. Taken together, these findings suggest that ADT induces cellular senescence processes accompanied by secretory phenotypes and anti-oxidant responses in prostate. These cellular changes may be attractive targets for preventing endocrine resistance in prostate cancer. (C) 2016 Elsevier Ltd. All rights reserved.