Kawata Hirotoshi, Kamiakito Tomoko, Nakaya Takeo, Komatsubara Maiko, Komatsu Kenji, Morita Tatsuo, Nagao Yasumitsu, Tanaka Akira
Department of Pathology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
Department of Urology, Jichi Medical University, Shimotsuke, Tochigi, Japan.
J Steroid Biochem Mol Biol. 2017 Jan;165(Pt B):219-227. doi: 10.1016/j.jsbmb.2016.06.007. Epub 2016 Jun 18.
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)-β-Gal activity in prostate glands, as well as the expressions of p27 and p53, in a mouse castration model. In line with this, the expressions of p21 and p27 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-β-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.
内分泌抵抗是前列腺癌中的一个主要问题。最近的研究表明，细胞可塑性在治疗抵抗中起关键作用。然而，对于雄激素剥夺治疗（ADT）后人前列腺癌的细胞变化知之甚少。在本研究中，我们调查了细胞衰老、衰老相关分泌表型（SASPs）和抗氧化反应。在小鼠去势模型中，激素去除上调了前列腺中衰老相关（SA）-β-半乳糖苷酶活性以及p27和p53的表达。与此一致的是，ADT后人非病理性前列腺组织中p21和p27的表达上调程度明显高于未治疗的标本。在一项关于SASP标志物的研究中，ADT后人非病理性前列腺组织中IL6和IL8的表达上调程度也高于未治疗的标本。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。值得注意的是，抗氧化剂NAC处理显著抑制了雄激素敏感的人前列腺癌LNCaP细胞中的SA-β-半乳糖苷酶活性。在对抗氧化反应基因的免疫组织化学分析中，ADT后人前列腺组织和癌标本中激素去除后NRF2和NQO1的上调程度高于未治疗的标本或去势后小鼠前列腺组织。综上所述，这些发现表明ADT诱导前列腺细胞衰老过程，伴有分泌表型和抗氧化反应。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。
